Serum brain‐derived neurotrophic factor and vitamin D: Two concordant players controlling depression among alopecia areata and vitiligo patients: A case–control study

Depression is a common psychiatric comorbidity among chronic dermatology patients. There is extreme lacking in the research studying biomarkers responsible for it. Both brain‐derived neurotrophic factor (BDNF) and vitamin D have a significant role in the development of depression.


| INTRODUC TI ON
Alopecia areata (AA) and vitiligo are multifactorial autoimmune diseases. One possible detrimental effect of these diseases, as a result of the aesthetic outcomes, is the increased risk of psychiatric complications such as depression and anxiety. 1,2 Neurotrophic factors are essential regulators that control differentiation, maturation, and survival of neurons. Brain-derived neurotrophic factor (BDNF) is profusely distributed in the brain and periphery (including human serum and plasma). It can modify serotonin and other neurotransmitters' pathways that have a role in the pathophysiology and treatment of depression and anxiety. Hence, BDNF can be a helpful marker for prevalence, and improvement of depressive symptoms; however, it cannot be used as a diagnostic indicator of major depression. 3 Although BDNF might play a role in the pathogenesis of some skin diseases that are aggravated by stress such as psoriasis 4  with the development of hair disorders. 7 Also, vitamin D is known to affect maturation, differentiation, proliferation, migration, survival, and melanin production of melanocytes. 8 Vitamin D deficiency affects the production and release of neurotrophic factors and some neurotransmitters in the central nervous system through membrane-associated and nuclear vitamin D receptors. Thus, it may be an additional risk factor for enhancement of psychological disorders such as depression. 9 Therefore, this research was implemented to assess BDNF and vitamin D serum levels in patients with different clinical varieties of AA, vitiligo, and control subjects correlating them with depression and quality of life.

| Clinical assessment
Patients' data were reported including age, gender, age of onset, disease duration, progression, and family history of similar condition.

| Alopecia patients' assessment
Diagnosis of AA was made clinically based on the presence of one or more well-defined patches of hair loss on the scalp with or without involvement of other body areas. Dermatologic examination was done to determine the clinical variants of alopecia (patchy, totalis, or universalis), its severity using Severity of Alopecia Tool (SALT score) 10 which was graded from S0 (no hair loss) to S5 (100% hair loss) and activity using Alopecia Areata Progression Index (AAPI). 11 in children (4-16 years). It ranged between 0 (no effect) and 30 (extremely large effect on patient's life). 14 The levels of vitamin D were labeled as deficient (<20 ng/mL), insufficient (20-29.99 ng/mL), and sufficient (≥30 ng/mL). 15

| Statistical analysis
Groups were compared using chi-square (qualitative variables), t-test (normally distributed quantitative variables), Mann-Whitney test (two non-normally distributed groups of quantitative variables), and Kruskal-Wallis test (three or more non-normally distributed groups of quantitative variables). Sperman's correlations were done to test linear relation between quantitative variables. Significance set point was P value ≤0.05.

| Studied population and their clinicodemographic data
This case-control study included three groups (30 AA patients, 30 vitiligo patients, and 30 control subjects). All groups were age and sex matched.

| Alopecia patients
Their age ranged between 7 and 55 years with a mean of (28.3 ± 13.7).
Most of the cases presented with NSV 80%. VASI score ranged between 0.50 and 99.5 with a mean of (23.7 ± 34.1), while VIDA score ranged between −1.00 and 4.00 with a mean of (1.40 ± 1.86).

| Comparison between patients and controls regarding serum BDNF and serum vitamin D
Both serum BDNF level and vitamin D were significantly lower in both patients compared to controls (p = 0.001 for all). Vitamin D level was deficient or insufficient in the majority of alopecia (86.6%) and vitiligo (90%) patients compared to controls (p = 0.001 for both).
Furthermore, mean vitamin D was significantly lower in vitiligo compared to alopecia patients (p = 0.009) ( Table 1).

| Associations and correlations of serum BDNF and serum vitamin D with clinical data of studied patients
Among alopecia patients, both serum BDNF and serum vitamin D did not show any significant association with gender, family history, or course of the disease (p value > 0.05). However, there was a significant association of both markers with alopecia type and SALT score grading. Serum BDNF showed gradual decrement from   Also, serum vitamin D showed a significant negative correlation with each of VIDA score (p = 0.03), BDI scale (p = 0.005), and DLQI (p = 0.01).
However, both serum BDNF and vitamin D did not show a significant correlation with VASI score ( Table 3). No significant correlations have been reported for both markers regarding age of patients or age of onset of disease in both alopecia and vitiligo patients ( Tables 2 and 3).

| Relationship between degree of depression and serum BDNF and vitamin D levels
Among patients, a significant association between degree of depression and both mean serum levels of BDNF and vitamin D has been noted. Both were significantly lower in cases with severe and moderate depression than mild ones ( Table 4).

| Correlation between serum BDNF and serum vitamin D
Serum BDNF correlated positively with serum vitamin D in both alopecia and vitiligo patients (p = 0.001 for both) (Figure 2).

| DISCUSS ION
Although vitiligo is not contagious, its associated psychological problems such as low self-esteem, bad effect on sexual relations, Similarly, all vitiligo patients had depression. This agrees with many previous studies, 23,24 but comes in the contrary to other studies. 16,25 Prevalence of depression varies among the studies depending on the diagnostic criteria or tools used and is also related to different genetic, cultural, religious, and environmental factors.
Although there are many studies concerning incidence and prev- There have been clinical studies that proved potential associations between low BDNF levels and major depressive disorders.
They also noted improvement in BDNF levels after effective treatment. Thus, serum BDNF may be considered as a good biomarker for major depressive disorders. 28   In this study, serum vitamin D correlated positively with BDNF.
This was explained by the significant role of active vitamin D in CNS. The enzyme 1, α-hydroxylase, which is the key enzyme in the synthesis of vitamin D, is found in the CNS and is associated with changes in the formation and release of neurotrophic factors. 40 Also, by enhancing serotonin-synthesizing gene transcription, vitamin D modifies synthesis and release of neurotrophic factors. 41 Furthermore, vitamin D3 supplementation is found to significantly raise BDNF level and acetylcholinesterase activity, and decreases oxidative stress and apoptosis in rats' brain. This influence might be related to direct alterations in BDNF gene transcription. 42 In conclusion, this study may indicate a potential combined effect of serum BDNF and vitamin D on the comorbid depression among AA and vitiligo patients. This might support the therapeutic benefits of vitamin D supplementation, since it may raise serum BDNF level and therefore improves depression symptoms. Thus, we suggest that vitamin D supplementation will not only improve clinical condition of alopecia and vitiligo patients as proven in previous studies, but also may improve their mood. Further research focusing on therapeutic values of vitamin D and BDNF in such patients is in need for evaluation.

AUTH O R CO NTR I B UTI O N S
NM and IS designed the research study and were responsible for data analysis, literature review, manuscript writing, and review. AZ performed the psychological assessment of patients. SM performed the investigations. AM and AM performed the clinical assessment, collected the data, and supplied the essential reagents. All authors have read and approved the final manuscript.

E TH I C S S TATEM ENT
The research was done after approval by local ethics committee.
This article has not been previously published, nor sent for another journal for consideration of publication.

FU N D I N G I N FO R M ATI O N
Nil.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors have no conflicts of interest to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.