|DR. G C BORAL AWARD PAPER
|Year : 2017 | Volume
| Issue : 1 | Page : 14-20
Role of Vitamin D supplementation in patients with depressive disorders and hypovitaminosis D: A longitudinal study
Naresh Nebhinani1, Praveen Sharma2, Navratan Suthar1
1 Department of Psychiatry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
2 Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
|Date of Web Publication||14-Jul-2017|
Department of Psychiatry, All India Institute of Medical Sciences, Jodhpur - 342 005, Rajasthan
Source of Support: None, Conflict of Interest: None
Background and Aim: Available literature is inconsistent for the role of Vitamin D supplementation in depression. With scarcity of Indian data, we aimed to study Vitamin D deficiency in patients with depression, its association with time to remission and role of Vitamin D supplementation. Methods: A total of 158 outpatients with depressive disorders were consecutively assessed for Vitamin D deficiency, severity of depression, physical activity, and nutritional habits and followed-up for 1 year. Eighty-seven patients completed follow-up for 1 year (55% retention). Results: Mean serum Vitamin D level was 11.9 ng/ml and the majority of patients (85%) had Vitamin D deficiency (<20 ng/mL). Significant predictors of hypovitaminosis D were being female, unemployed or homemaker, from nuclear family and with a smaller height. Vitamin D deficient patients took significantly longer time in remission than nondeficient patients (2.86 months vs. 1.35 months, P= 0.006). Patients with Vitamin D deficiency received Vitamin D supplementation and subsequently their time to remission was comparable to nondeficient group. Conclusions: The majority of patients had Vitamin D deficiency, took a longer time to remission and reported improvement with Vitamin D supplementation. It signifies the importance of treating hypovitaminosis D for effective management of depression, to avoid delay in response, and incomplete remission.
Keywords: Depression, hypovitaminosis D, India, time to remission, Vitamin D
|How to cite this article:|
Nebhinani N, Sharma P, Suthar N. Role of Vitamin D supplementation in patients with depressive disorders and hypovitaminosis D: A longitudinal study. J Mental Health Hum Behav 2017;22:14-20
|How to cite this URL:|
Nebhinani N, Sharma P, Suthar N. Role of Vitamin D supplementation in patients with depressive disorders and hypovitaminosis D: A longitudinal study. J Mental Health Hum Behav [serial online] 2017 [cited 2017 Dec 14];22:14-20. Available from: http://www.jmhhb.org/text.asp?2017/22/1/14/210712
| Introduction|| |
Depression is a major public health problem and occurs in persons of all ages, and is associated with increased morbidity, soaring costs for treatment and reduced productivity and quality of life., At present, it is the second common cause of disability, and projected to become the leading cause of disease burden and morbidity worldwide by 2030.
Furthermore, stigma, poor acceptability of psychiatric treatment, side effects of antidepressants are resulting in poor treatment adherence and high relapse rate of depression. Nutritional deficiency, especially of Vitamin D, is highly prevalent and potentially modifiable. Globally about 1 billion people have Vitamin D deficiency. Vitamin D is involved in numerous brain processes including neuroimmunomodulation, neuroprotection, neuroplasticity, regulation of neurotrophic factors, and making it biologically plausible to be associated with depression.
Hoang et al. assessed 12,594 healthy adults and found association of Vitamin D deficiency with depressive symptoms, especially in persons with history of depression. Two longitudinal studies have shown that low Vitamin D status at baseline may predict the development of depression in future.,
Sepehrmanesh et al. in a randomized, double-blind, placebo-controlled clinical trial reported significant improvement in depression with 8-weeks Vitamin D supplementation compared to placebo. In double-blind, randomized, placebo-controlled trial for 8-weeks, the Vitamin D + fluoxetine combination was found better than fluoxetine alone in reducing depression. Therefore, Vitamin D supplementation could provide cost-effective alternative for treating depression.
Several Indian studies have reported high prevalence of Vitamin D deficiency across India, including in healthy, middle-aged health care professionals (79%). With our best efforts, we could not find out any study from India on the role of Vitamin D supplementation in patients with depression.
High prevalence of depression as well as Vitamin D deficiency in general population, potential impact of Vitamin D deficiency on treatment and outcome of depression, lack of Indian data on this association, and wider acceptability, negligible side effects and cost effective approach with Vitamin D supplementation have given us impetus to study in this area and to fill the research gap with Indian data. The present study was aimed to assess Vitamin D status in patients with depression, its association with time to remission, and role of Vitamin D supplementation in the outcome of patients with depressive disorders.
| Methods|| |
The study was approved by the Institutional Ethics Review Committee. The study was carried out at the psychiatry outpatient clinic of a multi-specialty tertiary care hospital in North-Western India. The study sample comprised consecutive patients, of either gender aged between 18 and 60 years, with depressive disorders ( first episode depression, recurrent depressive disorder, and dysthymia) as per International Classification of Diseases, Tenth Revision (ICD-10) consulted to Psychiatry outpatient clinic from March to July 2015. Diagnostic confirmation was done by Mini International Neuropsychiatric Interview (MINI).
All the patients with depressive disorder were approached, excluding patients with bipolar depression, psychotic depression, and any other comorbid psychiatric or chronic physical disorders. Written informed consent was sought from all the patients. The assessment was done at their first visit to psychiatry outpatient clinic.
Totally 158 patients with depressive disorders were consecutively recruited and assessed for their severity of depression, functionality score, physical and nutrition habits score, obesity (as per Asian criteria body mass index (BMI) ≥25) and serum Vitamin D level. They were followed up monthly for 1 year. Out of 158 patients, 87 patients continued regular follow-ups for 1 year (55% retention rate). Therefore, we have used the data of those 87 patients for final analysis.
Including demographic and clinical profile sheet following instruments were used:
Mini International Neuropsychiatric Interview
The MINI is a clinician based, brief structured interview for diagnosis of a major axis I psychiatric disorders in Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV) and ICD-10 and divided into modules corresponding to diagnostic categories. MINI is compared with Structured Clinical Interview for DSM-III-R-patient version and Composite International Diagnostic Interview for ICD-10 and found to have high validity and reliability.
Hamilton Depression Rating Scale
It is a clinician-rated scale, with 17 items and each item is rated from 0 to 4, according to intensity and frequency of symptoms in the past few days.
Health Promoting Lifestyle Profile-II
It has been used extensively to explore health promoting lifestyle variables and found to have high construct validity and reliability. It is a 52-item self-report instrument, on likert scale from 1 to 4 with 1 = never, 2 = sometimes, 3 = often, and 4 = routinely. We have used two subscales, that is, physical activity and nutritional habit containing 8 and 9 items, respectively, with total score ranging from 17 to 68.
Global Assessment of Functioning Scale
It was developed to rate Axis-V of DSM diagnostic system. It measures overall functional status in relation to psychiatric symptoms.
Vitamin D status was measured by assessing circulating levels of serum 25-hydroxyvitamin D3 (25(OH) D) level, which reflects total Vitamin D from dietary intake and sunlight exposure, and including the conversion of Vitamin D from adipose stores in the liver. Therefore, it is the best indicator of overall Vitamin D status. Fasting blood samples were obtained in the morning from 10 am to 1 pm and kept frozen at 80°C and never thawed before analysis. Serum 25(OH) D was measured using chemiluminescence essay by DiaSorin. Vitamin D deficiency is defined as a level <20 ng/mL.
The number of sunlight hours in the 12 weeks preceding blood drawing was assessed, as a possible factor affecting serum Vitamin D level. As a standard protocol, we have prescribed antidepressants to all the study participants, commonly selective serotonin reuptake inhibitor (SSRI), with escitalopram being most common agent. Patients with hypovitaminosis D were given Vitamin D supplementation as per standard protocol one sachet of cholecalciferol (Vitamin D3) 60,000 units weekly for 8 weeks and later once a month to maintain the level.
SPSS version 14.0 for Windows (Chicago, Illinois, USA) was used for analysis. Categorical variables were analyzed with frequencies and percentages, whereas continuous variables were analyzed with mean and standard deviation. Subjects with and without hypovitaminosis D were compared using Chi-square test and t-tests and in case of skewed data nonparametric tests (Mann–Whitney U-test for continuous variables and Fisher exact test for categorical variables) were employed. Association of Vitamin D level and Vitamin D deficiency with demographic and clinical variables was assessed through correlational analysis. Predictors of hypovitaminosis D were assessed using binomial logistic regression analysis.
| Results|| |
Since our outcome of interest was time to clinical remission (i.e., when treatment of depression results in removal of essentially all symptoms, as defined in Stahl's essential psychopharmacology) and its association with Vitamin D status, therefore we compared demographic and clinical profile of patients who continued regular follow-up for 1 year (n = 87) with patients who were dropped out before 1 year (n = 71). Both the patient groups were similar for demographic profile, clinical variables, Vitamin D levels, functionality, physical activity, and nutritional scores.
Finally, we have analyzed the data of 87 patients who continued regular follow-up for 1 year. As depicted in [Table 1], mean age was 34 years. Nearly, two-third of patients were females, unemployed or homemaker, from extended or joint families, and urban locality. The majority of patients were married, and Hindu by religion.
The mean age of onset of depression, duration of depressive disorder, and monthly sun exposure were 31 years, 36 months, and 47 h, respectively. First episode depressive episode was the most common psychiatric disorder (77%), followed by recurrent depressive episode and dysthymia. Mean Hamilton Depression Rating Scale score was 17 with moderate to severe depression in half of the patients [Table 2].
Profile of hypovitaminosis D
Nearly one-third of patients were obese (BMI ≥ 25) (36.8%). Mean serum Vitamin D level was 11.9 ng/ml. The majority of patients were Vitamin D deficient (85%). Males had significantly greater Vitamin D levels than females (13.26 ± 7.08 vs. 10.87 ± 6.13, t = 2.25, P= 0.026). Hindus had significantly greater Vitamin D levels compared to Muslims (12.30 ± 6.72 vs. 8.41 ± 4.56, t = 2.44, P= 0.016). Serum Vitamin D level was positively associated with their height (correlation coefficient = 0.249, P= 0.002), sun exposure (correlation coefficient = 0.215, P= 0.012), and negatively associated with BMI (correlation coefficient = −0.201, P= 0.011).
As depicted in [Table 3], patients with Vitamin D deficiency (n = 74) were compared without Vitamin D deficiency (n = 13). Both the groups were comparable for age, education, income, religion, and locality, sun exposure time, duration of depression, weight, BMI, obesity, physical activity, functionality, nutritional habits, and depression severity scores.
|Table 3: Comparison of demographic, clinical profile among patients with Vitamin D deficiency versus without Vitamin D deficiency|
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Patients with hypovitaminosis D had a greater proportion of females, unemployed or homemaker, and were from nuclear family, smaller in height, and took longer time in remission of depression, compared to patients with normal Vitamin D level [Table 3].
Predictors of hypovitaminosis D
Predictors of hypovitaminosis D were assessed by using simple binary logistic regression analysis. As shown in [Table 4], significant predictors of hypovitaminosis D were female gender, unemployment, nuclear family and smaller height.
Association of hypovitaminosis D with time to remission
Patients with hypovitaminosis D took significantly longer time in remission compared to patients with normal Vitamin D levels (2.86 months vs. 1.35 months, Mann–Whitney U value = 252.5, P= 0.006) [Table 3]. Majority of patients with hypovitaminosis D were given Vitamin D supplementation as per standard protocol-one sachet of cholecalciferol (Vitamin D3) 60,000 units weekly for 8 weeks and followed by once a month dose to maintain the level.
Their blood sample for Vitamin D estimation was drawn at first visit, but owing to reporting time and monthly follow-up, Vitamin D supplementation was started nearly 1 month after their first contact.
Time to remission in patients with Vitamin D deficiency after supplementation was longer than patients with normal Vitamin D levels, but the difference was statistically not significant (1.95 months [standard deviation (SD) 2.24 months] vs. 1.35 months [SD 0.57 month], Mann–Whitney value = 160.0, P= 0.36).
| Discussion|| |
Baseline low Vitamin D level is found to be associated with developing depression over the time , and the same is also supported by several systematic reviews and meta-analysis.,, Meta-analysis of data from more than 50,000 study participants found a significant inverse association between serum 25(OH) D levels and the risk of depression. The odds ratio for having a current depressive episode was 1.8-fold higher in individuals with deficient Vitamin D compared to those with sufficient Vitamin D. A systematic review and meta-analysis of cohort studies by Anglin et al. reported significantly increased risk of developing depression with low Vitamin D levels (hazard ratio = 2.21, P< 0.001). On the other side, depression may also be a risk factor for developing Vitamin D deficiency, as depressed people may consume less nutritious diet, stay indoors, and exercise less; all these health behaviors contribute to hypovitaminosis D.
Given the high prevalence of both Vitamin D deficiency and depression, their association has significant public health implications. Vitamin D supplementation could play a significant role in the treatment of depression, and it has been supported by world literature,,,,,,, but we could not find any study from India. Index study is an attempt to fill this gap in literature.
Similar to earlier study by Dana-Alamdari et al., majority of our patients had Vitamin D deficiency (85%). In the present study, hypovitaminosis D was seen more in unemployed or homemakers, female patients, with smaller height, and from nuclear family. To elaborate further, unemployed or homemaker patients and females were less exposed to sun, patients with smaller height were having lesser body surface area, therefore having lesser production of Vitamin D with sun exposure. Patients from nuclear family might have lesser dietary intake of Vitamin D rich food. Other association of Vitamin D status was found with religion, but it might be associated with dietary pattern directly or indirectly.
Collin et al. reported lower probability of recurrent depressive symptoms with ≥10 ng/mL level of 25(OH) D. In index study, we did not find such association on comparing our patients with first episode versus recurrent episode of depression. Grudet et al. found significantly lower Vitamin D level in suicide attempters compared to depressed nonsuicidal patients. We could not find such association of Vitamin D level in our patients with suicidal ideation, as the majority of them had suicidal ideas but very few of them had suicide attempt in past.
Milaneschi et al. and Polak et al. reported inverse association of Vitamin D with depression severity. While similar to Dana-Alamdari et al., index study could not find such association. Milaneschi et al. reported greater risk (1.74 times) of developing depression in Vitamin D deficient patients and greater duration of depressive symptoms, compared to patients with normal Vitamin D levels. Similar to Milaneschi et al., index study reported longer time to remission in Vitamin D deficient patients. Hoang et al. found lesser Vitamin D levels in patients who did not engage in a regular physical activity, while we could not find any association between Vitamin D and physical exercise.
Similar to earlier studies,, we have also reported better response of augmentation with Vitamin D supplementation in patients with Vitamin D deficiency. After supplementation, their time to remission was comparable to patients without Vitamin D deficiency. This support the importance of timely assessment and treatment of hypovitaminosis D and role of Vitamin D supplementation in patients with depression as effective augmentation strategy, for achieving faster clinical remission. As a standard protocol we have prescribed single antidepressant, commonly SSRI, with escitalopram being most common agent, and in case of Vitamin D deficiency, we have added sachet cholecalciferol 60,000 units weekly for 8 weeks, and monthly dose thereafter. Thus, we have used Vitamin D as an augmentation agent and not used it as a monotherapy.
Augmentation strategies in depression treatment are being used commonly in patients with incomplete remission  or the presence of subsyndromal symptoms. Co-administration of nutraceuticals or nutritional agents may also enhance antidepressant effects, either by synergistically augmenting effects of antidepressants or by other biological effects., Many nutraceuticals are cost effective, safe and evidence-based augmenting agents for depression treatment including Vitamin D supplementation. Similar to earlier evidence, we have found Vitamin D supplementation safe and effective as an adjunctive treatment in depressive disorder with hypovitaminosis D.
Association of Vitamin D deficiency with cognitive/affective depressive symptoms  and greater risk of cognitive impairment in patients with depression  in earlier studies suggest potential role of Vitamin D supplementation in preventing cognitive impairment. Prospective longitudinal studies are needed to generate evidence for the same.
Although in few studies Vitamin D status was not found to be associated with depression  and no effect was found with Vitamin D supplementation. To explain the inconsistencies in RCTs reporting efficacy of Vitamin D supplementation in reducing depression, a meta-analysis by Gowda et al. highlighted that most of such studies focused on individuals with low levels of depression and sufficient serum Vitamin D at baseline and used different Vitamin D doses with a varying degree of intervention duration. In a meta-analysis of all studies without flaws, Spedding  demonstrated a significant improvement in depression with Vitamin D supplements, with effect size of 0.78, which was comparable to that of anti-depressant medication.
| Conclusion|| |
To conclude majority (85%) of patients with depression had Vitamin D deficiency. It was seen more in unemployed or homemaker, females, patients with smaller height, and from nuclear family. These all factors were also found significant predictors for hypovitaminosis D. Vitamin D deficient patients took significantly longer time in remission than nondeficient patients. All the patients with Vitamin D deficiency received supplementation and subsequently their time to remission was comparable to nondeficient group. It signifies the need for timely assessment and treatment of hypovitaminosis D for effective management of depression to avoid delay in response, treatment resistance, incomplete remission, or residual symptoms.
Index study has following limitations: Hospital based sample, smaller sample size for patients with normal Vitamin D status, causal association cannot be determined between Vitamin D levels and depression and due to logistic issues Vitamin D supplementation was started nearly 1 month after their first contact and we could not repeat Vitamin D serum levels after the supplementation. Future studies should be conducted in larger sample from hospital and community, with healthy controls, prospective and multicentric study design, and detailed exploration of physical activity, dietary patterns, sun exposure and other health promoting lifestyle behaviors and future research should attempt to overcome above limitations.
To the best of our knowledge, this is the first Indian study reporting important role of Vitamin D supplementation in the treatment of depression. After filling this research gap with positive findings, Vitamin D supplementation is likely to be one of the most cost-effective treatment in psychiatry, with negligible side effects. Therefore, timely assessment of Vitamin D level and supplementation in depression is of considerable importance.
Our sincere gratitude to patients, their families, laboratory staff for their kind cooperation. Special thanks to Dr. Vrinda Pareek, Dr. Deep Kanwar, Dr. Mukesh Gehlot for patient recruitment and data intake and Dr. Purvi Purohit, Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India for her generous laboratory support.
Financial support and sponsorship
This project has received intramural grant from All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]