East Asian Arch Psychiatry 2022;32:51-6 | https://doi.org/10.12809/eaap2209

ORIGINAL ARTICLE

Krittisak Anuroj, MD, Thai Board of Child and Adolescent Psychiatry, Department of Psychiatry, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok province, Thailand

Address for correspondence: Krittisak Anuroj, Thai Board of Child and Adolescent Psychiatry, Department of Psychiatry, Faculty of Medicine, Srinakharinwirot University, Ongkharak Campus, 62 Moo 7 Ongkharak subdistrict, Ongkharak district, Nakhon Nayok province, Thailand. Postal code: 26120. Email: thymelancille@gmail.com

Submitted: 30 January 2022; Accepted: 8 August 2022

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Introduction

Vitamin D is a group of fat-soluble micronutrients. Vitamin D deficiency is associated with macrophage dysfunctions, autoimmune diseases, multiple sclerosis, colorectal cancer, congestive heart failure, and type 1 diabetes mellitus.¹ It is also associated with mental disorders, particularly schizophrenia,² but its roles in depressive disorder, which involves regulation of neuroinflammation and trophic factors, remain controversial.^3-6

The estimated average vitamin D requirement in adult is 400 IU per day.⁷ Vitamin D can be acquired through photosynthesis and ingestion. Exposure of arms and face to the sun for 5 to 30 minutes (depending on location and skin pigmentation) twice a week is considered adequate.⁸ Few foods contain natural vitamin D; dietary vitamin D intake is difficult to determine and only contributes to 10% to 40% of recommended dietary intake.^1,9 Sunlight is thus the major source. The conventional cut-off for vitamin D deficiency is <20 ng/mL (based on the ability to prevent rickets). A cut-off of <12 ng/mL was proposed by the US Institute of Medicine.¹⁰ In Thailand, the prevalence of vitamin D deficiency (based on the cut-off of <20 ng/mL) has been reported to be 0.7% to 45%,^11-13 compared with the worldwide prevalence of 1% to 80%, depending on the altitude and clothing (Muslim women tend to have lower vitamin D levels).¹⁴ During the COVID-19 pandemic, with implementation of lockdowns, quarantines, restrictions of mobility, work from home, and online learning, the prevalence in Thailand has increased to 19% to 78%.^15,16 In Libyan medical students during the pandemic, the prevalence (<20 ng/mL) was 74%.¹⁷

This study aims to evaluate the prevalence of vitamin D deficiency in year 4 and year 5 medical students during the pandemic and to determine the association between vitamin D level and depressive symptoms.

Materials and methods

This study was approved by the Human Research Ethics Committee of Srinakharinwirot University (reference: SWUEC-376/2563F). Informed consent was obtained from each participant. Medical students of year 4 and year 5 rotating in the Srinakharinwirot University Hospital in Nakhon Nayok province, Thailand who had no diseases associated with vitamin D deficiency (chronic kidney disease, malabsorption, parathyroid hormone disorders, etc) and had not taken vitamin D supplement in the past year were invited to participate.

The sample size calculation was based on a study of Thai orthopaedic surgeons during the pandemic.¹⁵ 92 participants were needed for prevalence estimation with 90% confidence interval and 5% precision value.

In May 2021, blood specimens were collected between 12:00 to 13:00 without requirement for prior fasting.¹⁸ Specimens were centrifugated, and serums were frozen at -20°C and thawed before ELISA. Participants were asked to complete a questionnaire to record demographic data: age, sex, family income, class year, grade point average, current and history of psychiatrist-diagnosed psychiatric illnesses, other underlying diseases, and perceived difficulties in academic, relationship, substance use, and social supports (total score ranges from 0 to 12; higher scores indicate more perceived difficulties).

Students’ depressive symptoms were assessed using the Thai version of Patient Health Questionnaire— adolescent (PHQ-A), which comprises nine items measured in a 4-point Likert scale. The PHQ-A has been validated in both secondary and college students. Its content is more relatable to college students; it includes an irritability feature in the item measuring affective disturbance, which corresponds to the A1 item of DSM-5 for major depressive disorder in adolescents. Total score ranges from 0 to 27; a cut-off score of ≥10 indicates presence of moderate depressive symptoms.¹⁹

Association between low vitamin D levels (insufficiency and deficiency) and presence of depressive disorder was determined using the Fisher exact test. Correlation between vitamin D level and PHQ-A score was determine using the Spearman rank correlation coefficient. Linear regression analysis was used to determine independent predictors of presence of depressive symptoms. Owing to the significant difference in vitamin D level between year 4 and year 5 students, post-hoc analysis was performed using independent t-test.

Results

A total of 63 female and 36 male medical students participated. 47.5% were year 4 and 52.5% were year 5. Ten participants self-reported to have psychiatric illness: major depressive disorder (n = 7), adjustment disorder (n = 2), and obsessive compulsive disorder (n = 1). Twelve participants were identified to have depression through elevated PHQ-A scores (three of them also self-reported to have depression). Ten participants reported to have allergy, whereas 12 participants reported to have other underlying diseases: thalassemia trait (n = 3), migraine (n = 2), endometriosis (n = 1), polycystic ovary syndrome (n = 1), patent foramen ovale (n = 1), history of hyperthyroidism (n = 1), essential tremor (n = 1), history of deep venous thrombosis (n = 1), and iron deficiency anaemia (n = 1) [Table 1]. No participant reported pregnancy or breastfeeding.

The mean vitamin D level was 21.7 ± 12.7 ng/mL, with a right-skewed distribution. Using the conventional cut-off of <20 ng/mL, 52.5% of participants had vitamin D deficiency, whereas 17.2% had vitamin D insufficiency (20-30 ng/mL) and 30.3% had adequate vitamin D levels (>30 ng/mL). Using the Institute of Medicine cut-off of <12 ng/mL, 26.3% of participants had vitamin D deficiency, whereas 26.3% had vitamin D insufficiency (12-20 ng/mL) and 47.5% had adequate vitamin D level (>20 ng/mL). The mean vitamin D level in year 4 students was significantly lower than that in year 5 students (12.2 ± 5.3 vs 30.2 ± 11.3 ng/mL, t = -10.00, p < 0.01). Vitamin D level was associated with age (r = 0.38, p < 0.01) and sex (marginally) [t = -1.80, p = 0.07] but not with family income, grade point average, total perceived difficulties score, presence of psychiatric/other underlying disease, or presence of depressive symptoms. In linear regression analysis, vitamin D level remained associated with the year of class after adjusting for age and sex (B = 18.67, p < 0.01), with Durbin- Watson statistics of 1.96 and adjusted R² of 0.50. Normally distributed errors were observed.

The mean PHQ-A score was 5.8 ± 4.3, with a right- skewed distribution. 16 participants were identified to have depression: 4 were mild (who self-reported to have depression) and 12 were moderate or higher (who had a PHQ-A score of >10) [Table 2]. Vitamin D deficiency/ insufficiency was not associated with presence of depression based on the cut-off of <20 ng/mL (p = 0.43) or the cut-off of <30 ng/mL (p = 0.38). Vitamin D level was not correlated with PHQ-A score (r = 0.03, p = 0.80). PHQ-A score was associated with total perceived difficulties score (Spearman coefficient = 0.44, p < 0.01), grade point average (Spearman coefficient = -0.21, p = 0.03), year of class (t = 10.34, p < 0.01), and sex (marginally) [t = -1.82, p = 0.07]. In stepwise regression analysis, only total perceived difficulties score remained a predictor for PHQ-A score. In linear regression analysis, vitamin D level was not associated with PHQ-A score after adjusting for total perceived difficulties score (B = -0.02, p = 0.46), with an adjusted R² of 2.42 and Durbin-Watson statistics of 2.02. Residual data were normally distributed.

Discussion

During the COVID-19 pandemic, the prevalence of vitamin D deficiency (<20 ng/mL) among Thai medical students was 52.5%, which is higher than the 0.7% to 45% among the Thai population before the pandemic^11-13 but is comparable with the 19% to 78% reported in other studies during the pandemic^15,16 and is lower than the 74% among medical students in Libya during the pandemic.¹⁷ Insufficient sunlight exposure may be a possible cause.

During the study period, Thailand implemented the zero COVID-19 policy, for which all university classes were delivered online. Year 4 students who moved up from preclinical studies and had all classes online may have lacked sun exposure from daily routines and attendance. The sleep-wake cycles in some students may have been chaotic (by studying at night). These could have accounted for their lower vitamin D levels. Year 5 students had half online classes and half on-site classes (to attend ward rounds and outpatient departments). Most year 5 students resided in dormitory, which is approximately a 15-minute trip to the hospital, and commuted between the hospital, library, and cafeteria during daytime. The estimated minimal outdoor time is about 30 to 40 minutes, which fulfils daily sunlight exposure requirement unless sunscreen or extra shades are used.^8,20 Year 4 students tended to dress casually (in T-shirts and shorts), whereas year 5 students wore more formal uniforms with a long gown for ward rounds. Despite this, year 5 students had higher mean vitamin D level; the difference is thus not contributed by occlusion from garments. The sun-occlusive dress code for Muslim women does not affect our participants who are Buddhists.

Differences in dietary intake is unlikely to cause differences in vitamin D levels between year 4 and year 5 students. Thai food in general lacks fortified and natural sources of vitamin D. The only commonly consumed food with vitamin D is chicken egg, which contains relatively low vitamin D (approximately 5% of recommended dietary intake per one egg yolk).²¹ Year 5 students usually are busier and may have less mealtime and thus consume more fast food. Family income was similar between year 4 and year 5 students and should not have affected students’ purchasing power.

Vitamin D deficiency increases long-term health susceptibility to chronic diseases.¹ For health prevention and promotion, those with reduced sunlight exposure during the pandemic should be evaluated for vitamin D deficiency, educated about daily requirement of sunlight exposure, and encouraged to have sunlight exposure in safe environments (such as apartment balcony or in open spaces with proper personal protection). Oral vitamin D supplement is also an alternative.

Participants with vitamin D deficiency/insufficiency were referred for oral vitamin D treatment (free of charge under the universal healthcare system), but only 28 of 69 reported to have received treatment. Reasons for the low turnout may include opting for non-pharmacological treatment, lack of time, self-treatment, and avoidance of clinical visits for fear of COVID-19 infection. Options for online consultation and contactless delivery of medicine may alleviate the fear of COVID-19 infection during the pandemic.

In the present study, the association between vitamin D level and depressive symptoms was not found, in contrast with previous observational studies that reported presence of such association.^3,4 The small sample size of present study may be underpowered to detect small effect sizes in regression models. The prevalence of depression among year 4 and year 5 medical students was 16.2%, which is similar to the 19.6% in Thai medical students but is significantly higher than the 0.2% in the general Thai population.^22,23 Being medical students could have accounted for a great variance on depression, eclipsing the effects of vitamin D deficiency. Other confounders associated with elevated depressive symptoms in medical students include relationship problems, sleep problems, academic difficulties, dissatisfactions with attending staff, unfavourable facilities, and dropout status.^23-25 Substances may also predispose to depression when in use or withdrawal. The total perceived difficulties score remained a predictor for depressive symptoms. Participants’ underlying disease or disease history was not associated with depressive symptoms, probably owing to heterogeneity or small effect size. Some potential confounders may not have been controlled. For example, the chaotic sleep-wake schedule could have decreased the effectiveness of family emotional support, whereas the online communication during lockdowns could have decreased the effectiveness of peer support.

The PHQ-A may not be sensitive enough to detect small difference in symptoms in those with milder condition. The use of assessment tools that are more accurate in detecting milder depressive symptoms may be more appropriate for future studies.

Vitamin D acts on nuclear level and protein transcriptions; little is known about the onset of Vitamin D deficiency on depressive symptoms. Past studies on chronic diseases presumed vitamin D statuses from altitude of residence, which indicated pathological changes from

chronic deficiency^1,26; this may also be the case with depression. It is unknown whether participants’ vitamin D deficiency was chronic or acute. In acute cases, biological pathologies necessary for depression to manifest may not have developed. Future studies with longitudinal monitoring can address the issue of delayed onset; proximal confounders (risk factors) and depression should be assessed regularly for accurate adjustments. Analyses of both the vitamin D level and duration of deficiency (dose × time) enable more robust evidence of association for delayed-onset condition. Assessments of biomarkers (such as inflammatory markers, kynurenine metabolites, and trophic factors) and functional imaging also enable more robust evidence of correlation between vitamin D status and depressive symptoms.

How vitamin D deficiency–related pathologies affect people with depression remains unknown. The deficiency may not be sufficient to act as precipitator of depressive episode in a normal person but may be capable of perpetuating an established pathology in a person with depression. Depression pathology is heterogeneous; the effect and correction of vitamin D deficiency can be stronger in those with neuroinflammations or disturbances in trophic factors. Future studies of different population groups are warranted, with subgroup analysis or moderation analysis on effect of clinical depression × vitamin D level on depressive symptoms.

There are limitations to the present study. The sample size was small and from a single centre. The power to detect associations with small effect sizes is limited. The small sample size precluded subgroup analyses on differential effects of vitamin D levels in normal versus clinically depressed groups. Our findings cannot be generalised to other populations. Association between vitamin D deficiency and delayed-onset depressive symptoms cannot be assessed owing to the cross-sectional design. The COVID-19 pandemic may have given rise to unexpected confounders. Larger multicentre longitudinal studies are needed.

Conclusion

The prevalence of vitamin D deficiency/insufficiency in Thai medical students during the COVID-19 pandemic was high (52.6% or 69.5%), probably owing to a lack of sunlight exposure. Nonetheless, vitamin D level was not associated with depressive symptoms, probably owing to the small sample size or delayed onset of depressive symptoms.

Contribution

The author designed the study, collected data, oversaw research assistants (in specimen collection, storage, assay), analysed the results, and prepared and revised the manuscript. The author had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflict of interest

The author has disclosed no conflicts of interest.

Funding/support

This study was supported by a research grant from Faculty of Medicine, Srinakharinwirot University.

Data availability

All data generated or analysed during the present study are available from the corresponding author on reasonable request.

Ethics approval

The study was approved by Human Research Ethics Committee of Srinakharinwirot University (reference: SWUEC-376/2563F).

References

1. Peterlik M, Cross HS. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest 2005;35:290-304. ^Crossref
2. Cui X, McGrath JJ, Burne THJ, Eyles DW. Vitamin D and schizophrenia: 20 years on. Mol Psychiatry 2021;26:2708-20. ^Crossref
3. Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry 2013;202:100-7. ^Crossref
4. Parker GB, Brotchie H, Graham RK. Vitamin D and depression. J Affect Disord 2017;208:56-61. ^Crossref
5. Zhu C, Zhang Y, Wang T, et al. Vitamin D supplementation improves anxiety but not depression symptoms in patients with vitamin D deficiency. Brain Behav 2020;10:e01760. ^Crossref
6. Okereke OI, Reynolds CF 3rd, Mischoulon D, et al. Effect of long- term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: a randomized clinical trial. JAMA 2020;324:471-80. ^Crossref
7. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. Washington (DC): National Academies Press (US); 2011.
8. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81^Crossref
9. Holick MF. Sunlight, UV radiation, vitamin D, and skin cancer: how much sunlight do we need? Adv Exp Med Biol 2008;624:1-15. ^Crossref
10. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011;96:53-8. ^Crossref
11. Hewison M, Bouillon R, Giovannucci E, Goltzman D, editors. Vitamin D. 4th edition. Boston: Elsevier; 2017.
12. Rajatanavin N, Kanokrungsee S, Aekplakorn W. Vitamin D status in Thai dermatologists and working-age Thai population. J Dermatol 2019;46:206-12. ^Crossref
13. Siwamogsatham O, Ongphiphadhanakul B, Tangpricha V. Vitamin D deficiency in Thailand. J Clin Transl Endocrinol 2014;2:48-9. ^Crossref
14. Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol 2014;144:138-45. ^Crossref
15. Phruetthiphat OA, Kusuwannakul N, Khuangsirikul S, Tutaworn T, Songpatanasilp T, Chotanaphuti T. Prevalence of vitamin D inadequacy among orthopedic surgeons. J Southeast Asian Med Res 2021;5:35-41^Crossref
16. Wongkhankaew N, Pongsatha S. A cross sectional study of serum vitamin D levels in perimenopausal and postmenopausal women working outdoors or indoors. J Med Assoc Thai 2021;104:1807-13.^Crossref
17. Msalati A, Bashein A, Aljaloh E, Murad G, Sedaa K, Zaid A. Prevalence of vitamin D deficiency in medical students. Mediterr J Pharm Pharm Sci 2022:55-64.
18. Moyad MA. Vitamin D: a rapid review. Urol Nurs 2008;28:343-9.
19. Panyawong W, Pawasuttipaisit C, Santitadakul R. Development of the Thai version of the Patient Health Questionnaire for Adolescents (PHQ-A) [in Thai]. Bangkok: Child and Adolescent Mental Health Rajanagarindra Institute; 2018.
20. Dowdy JC, Sayre RM, Holick MF. Holick’s rule and vitamin D from sunlight. J Steroid Biochem Mol Biol 2010;121:328-30. ^Crossref
21. Thai Department of Health. Dietary Reference Intake for Thais 2020. Bangkok: Ministry of Public Health; 2020.
22. Kittirattanapaiboon P, Tantirangsri N, Tanari A, et al. Prevalence of Mental Disorders and Mental Health Problems: Results from Thai National Mental Health Survey 2013. Nonthaburi: Beyond Publishing; 2013.
23. Limsricharoen K, Handee N, Chulakdabba S. Prevalence and associated factors of depression in second to sixth years medical students, faculty of medicine in Thailand [in Thai]. J Psychiatr Assoc Thai 2014;59:29-40.
24. Wongsiri K. Assessment of depression among medical students between medical education center and university hospital [in Thai]. Maharaj Nakhon Sri Thammarat Med J 2013;1:27-33.
25. Auchayasawat S. Prevalence and factor affecting depression in clinical medical students from a medical school in northeastern Thailand [in Thai]. Srinagarind Med J 2021;36:200-8.
26. Meeker S, Seamons A, Maggio-Price L, Paik J. Protective links between vitamin D, inflammatory bowel disease and colon cancer. World J Gastroenterol 2016;22:933-48. ^Crossref