J Clin Aesthet Dermatol. 2020;13(2)13–16
by Sherine Hosny Ahmed, MD; Amira Ahmed El-Kelish, MSc;
Neveen Abdel Hafeez, MD; and Shewikare Taweek El-Bakry, MD
All authors are with the Faculty of Medicine, Benha University in Benha, Egypt.
FUNDING: No funding was provided for this study.
DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article.
ABSTRACT: Background. Acne is one of the most common skin diseases and is frequently associated with depression, social isolation, and suicidal ideation. Some studies have investigated the link of either acne or depression and serum levels of vitamin B12 and folic acid (FA), but none appear to have examined the effect of these vitamins on acne patients with or without depression.
Objective. This case-control study sought to assess whether serum levels of vitamin B12 and FA could be considered possible predictors for depression and acne severity in patients with moderate and severe acne.
Methods. Forty patients with acne and 40 age- and sex-matched healthy volunteers were enrolled. Acne severity and depression were assessed according to the Global Acne Grading System (GAGS) and the Arabic version of the Beck Depression Inventory II (BDI-II), respectively. Five milliliters of blood was obtained by clean venipuncture to determine B12 and FA levels by way of double-antibody sandwich enzyme-linked immunosorbent assay.
Results. According to GAGS score, moderate acne was the most prominent form of the condition (55%), followed by severe (25%) and very severe (20%). Seventy percent of patients with acne had depression according to BDI-II score versus zero percent in the control group (p<0.001). Patients with moderate and severe acne in this study had significantly lower serum levels of vitamin B12 and FA when compared to controls (p=0.012 and p<0.001) and their levels showed a significant negative correlation with acne severity according to GAGS score.
Conclusions. Screening for vitamin B12 and FA deficiency can be particularly relevant in patients with acne to assess depression risk. Folate supplementation should be considered for patients with acne and comorbid depression.
KEYWORDS: Acne, GAGS, BDI, vitamin B12, folic acid, depression
Acne is one of the most common skin diseases, affecting more than 80 percent of adolescents and young adults globally.1 It can be extremely painful, disfiguring, and scarring, and can profoundly affect self-esteem and mental health in many patients. Acne is frequently associated with depression, social isolation, and suicidal ideation.2 Depression itself is a major mental health problem and is a leading cause of disability worldwide.3 Its symptoms increase dramatically during adolescence.4 Folic acid (FA) and vitamin B12 are water-soluble vitamins important for nerve and brain function and hematopoiesis; they are also known as cobalamin and vitamin B9, respectively.5 Vitamin B12 and FA, with their interrelated metabolism, are important for the maintenance of various metabolic pathways in the body. In cases of deficiency, adverse effects on cardiovascular, neurological, psychological, hematological, gastrointestinal, locomotor (i.e., musculoskeletal) and immunological systems can occur.6
Some studies have investigated the link between either acne or depression and serum levels of vitamin B12 and FA but, to the best of our knowledge, none of these assessed the effect of these vitamins on acne patients with or without depression.7,8 Therefore, we aimed to assess whether serum levels of vitamin B12 and FA could be considered possible predictors for depression and acne severity in patients with moderate and severe acne.
This was a case-control study conducted with 40 patients with acne (14 [35%] men and 26 [65%] women) and 40 age- and sex-matched healthy volunteers (16 [40%] men and 24 [60%] women). This study was approved by the Research Ethical Committee of our institute according to the relevant Declaration of Helsinki principles. Patients were selected from the dermatology outpatient clinic between June 9, 2018, and January 28, 2019. Patients diagnosed with any disease (e.g., Crohn’s disease, celiac disease, renal failure, diabetes, malignancy) or taking any medication (e.g., isotretinoin, methotrexate, sulfasalazine, proton pump inhibitors, H2 receptor blockers) or supplements known to affect vitamin B and/or FA levels three months prior to the study were excluded. All participants signed an informed consent form and were subjected to a thorough personal history review, including demographic characteristics, age of onset, duration of acne, and family history of acne. Acne severity and depression were assessed according to the Global Acne Grading System (GAGS)9 and the Arabic version of the Beck Depression Inventory II (BDI- II),10,11 respectively.
The BDI-II11 is a 21-item inventory that measures the severity of self-reported depression over the prior two weeks; its item content corresponds to criteria for the diagnosis of depressive disorders as specified in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition.12 Items are structured on a four-point scale, ranging from zero points (symptom not present) to three points (symptom strongly present). Thus, a BDI-II total score from 0 to 13 points represents normal to minimal depression, from 14 to 19 points indicates mild depression, from 20 to 28 points indicates moderate depression, and from 29 to 63 points indicates severe depression.
Five milliliters of blood was obtained by clean venipuncture. Samples were allowed to clot and serum samples were obtained and kept at -20°C until the time of runway for the determination of vitamin B12 and FA levels. All samples were studied on the same day and by using the same kit. Vitamin B12 and FA levels were determined by double-antibody sandwich enzyme-linked immunosorbent assay; in this study, the normal ranges for adults were 4.17 to 20ng/mL for FA and 117 to 1,158pg/mL for vitamin B12.
Statistical analysis. Data were collected, revised, coded, and entered into the Statistical Package for the Social Sciences version 20 software program (IBM Corp., Armonk, New York). Quantitative data were analyzed using means and standard deviations, while frequencies and percentages were considered when assessing qualitative data. Additional evaluations included the Student’s t-test for independent samples, chi-squared test for comparing categorical data, Pearson’s correlation coefficient to detect the relationship between two continuous variables, and Spearman’s correlation coefficient to measure the strength of association between two variables. Fisher’s exact test (F-test) was applied to comprehend the different proportions for one variable among other variables values. A p-value of less than 0.05 was considered to be statistically significant.
Ages of the participants in the acne group ranged from 16 to 28 years (mean: 19.8±3.0 years), while, in the control group, it ranged from 16 to 25 years (mean: 19.5±3.1 years). There was no significant difference in either the age or sex distribution pattern between the two groups (p=0.68 and p= 0.64, respectively).
Age of acne onset ranged from 13 to 17 years (mean: 14.4±0.92 years) and acne duration ranged from 2 to 11 years (mean: 5.4±2.7 years). Seventy percent of patients with acne had a negative family history and 30 percent had a positive history. According to GAGS score, moderate acne was the most prominent form (55%), followed by severe (25%) and very severe (20%).
According to BDI-II scores, 70 percent of the participants with acne also had depression versus zero percent in the control group, with a significant difference noted between the groups (p<0.001). Table 1 shows that acne severity had a significant effect on various degrees of depression. Furthermore, BDI-II score had insignificant (p>0.05) positive and negative correlation with GAGS score (r=0.292) and age of acne onset (r=-0.031), respectively. On the other hand, it showed a significant correlation with age of the patients and the duration of acne lesions (r=0.045 and r=0.046, respectively; p less than or equal to 0.05). BDI-II score was insignificantly higher in female participants than male participants and in those with positive family history versus those with negative family history (p greater than or equal to 0.05).
Patients with moderate and severe acne in this study had a significantly lower serum levels of vitamin B12 and FA compared to controls (p=0.012 and p<0.001, respectively) (Table 2) and their levels showed a significant negative correlation with acne severity according to GAGS score (r=-0.466 and -0.564, respectively) (p<0.05). Table 3 reveals a significant difference (p<0.05) when the cutoff values to vitamin B12 and FA are 50.2pg/mL and 2.47ng/mL, respectively. At this point, the areas under the curve (AUCs) were 0.663 and 0.744 for vitamin B12 and FA respectively, suggesting that both can be used as indicators for the early diagnosis of inflammation in patients with acne.
The median serum level of FA showed significant negative and positive correlations with BDI-II score (r=-0.579; p<0.001) and serum vitamin B12 level (r=0.479; p=0.002) in patients with moderate and severe acne. The AUC was greater than 0.625, which suggests that FA can be used to make an early diagnosis of depression in patients with moderate and severe acne vulgaris. Sensitivity and specificity values of this test were 85.7 percent and 83.3 percent at a cutoff value of 2.14ng/mL (Table 4).
It is noteworthy that 12 percent of the control group had a deficiency of vitamin B12 and FA compared to findings of 10.7 percent and 25 percent in the patient group, respectively.
In the present study, 70 percent of the patients with acne had depression according to BDI-II score, with a significant difference between both studied groups. This outcome was also detected in another study,2 as the authors reported that the rate of depression was 63.1 percent among 181 patients with facial acne; likewise, Awad et al13 reported a higher score of anxiety and depression among patients with acne relative to controls. Kang et al2 concluded that the more severe the acne is, the greater the suffering from depression, which was also detected in our study. BDI-II scores in the current study as well as in other studies were influenced by many factors including acne severity, age and sex of the patients, duration of acne lesions, and positive family history.2,14
Patients with moderate and severe acne in this study had significantly lower serum levels of vitamin B12 and FA compared to controls. This was also detected in two studies but with no significant difference seen between the studied groups.7,15 This difference might be due to the exclusion of male participants in one study7 and the inclusion of mild acne and different measuring techniques in the other.15 Furthermore, our study revealed a significant negative correlation between serum levels of vitamin B12 and FA and acne severity according to GAGS score, which was inconsistent with the results of Balta et al.16 This discrepancy might be due to methodological differences, as they included only patients with postadolescent acne.
The literature is inconsistent regarding the relation of vitamin B12 with depression; one study,8 in addition to our study, found that vitamin B12 doesn’t correlate with depressive symptoms, while another study17 stated the contrary. Further, there is compelling evidence of the relation between FA and depression, which was detected both in this study and in others.18,19 Goa et al20 elucidated the antidepressant effect of FA through increasing brain 5-hydroxytryptamine concentration, brain-derived neurotrophic factor and glutamate receptor 1 expressions, and repair of synaptic organization in the brain.
Although the percentages of participants in the control group with deficiencies of vitamin B12 and FA were comparable to those in other studies,5,21 it was still observed that patients with both acne and depression had the highest percentages of inadequate vitamin B12 and FA levels. To the best of our knowledge, we are the first to measure the serum levels of vitamin B12 and FA in patients with both acne and depression.
FA and vitamin B12 deficiencies are considered public health problems worldwide,22 especially in Egypt,23,24 and their deficiency causes hyperhomocysteinemia, which is an independent risk factor for endothelial dysfunction and coronary artery disease (CAD).25 Considering these findings alongside the results of the current study, there is compelling evidence that low levels of vitamin B12 and FA increase the risk of depression or even suicidal attempts as well as CAD in female patients with an early onset and long duration of moderate or severe acne and positive family history
Deficiencies of vitamin B12 and FA are risk factors for acne severity and depression, especially in people at risk (e.g., females with early-onset acne, long duration of moderate or severe acne, and positive family history).
Conducting screening for vitamin B12 and FA deficiency can be particularly relevant in patients with moderate and severe acne or in those who attempt to start any medications known to influence vitamin B12 and FA levels. Folate supplementation should be considered for patients with acne and comorbid depression.
- Ghodsi SZ, Orawa H, Zouboulis CC. Prevalence, severity, and severity risk factors of acne in high school pupils: a community-based study. J Invest Dermatol. 2009;129(9):2136–2141.
- Kang D, Shi B, Erfe MC, et al. Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis. Sci Transl Med. 2015;7(293):293ra103.
- Sockol LE, Epperson CN, Barber JP. Preventing postpartum depression: a meta-analytic review. Clin Psychol Rev. 2013;33(8):1205–1217.
- Wang H, Lin SL, Leung GM, et al. Age at onset of puberty and adolescent depression: “Children of 1997” birth cohort. Pediatrics. 2016;137(6). pii: e20153231.
- Galukande M, Jombwe J, Fualal J, et al. Reference values for serum levels of folic acid and vitamin B12 in a young adult Ugandan population. Afr Health Sci. 2011;11(2):240–243.
- Snow CF. Laboratory diagnosis of vitamin B 12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999;159(12): 1289–1298.
- Arora MK, Seth S, Dayal S. Homocysteine, folic acid and vitamin B12 levels in females with severe acne vulgaris. Clin Chem Lab Med. 2012;50(11): 2061–2063.
- Sachdev PS, Parslow RA, Lux O, et al. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med. 2005;35(4):529–538.
- Doshi A, Zaheer A, Stiller MJ. A comparison of current acne grading systems and proposal of a novel system. Int J Dermatol. 1997;36(6):416–418.
- Ghareeb AG. Manual of the Arabic BDI-II. Cairo, Egypt: Angle Press; 2000.
- Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation; 1996.
- Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Primary Care Version. Brian P, Quinn CSW. Prim Care Companion J Clin Psychiatry. 1999;1(2):54–55.
- Awad SM, Morsy H, Sayed AA, et al. Oxidative stress and psychiatric morbidity in patients with facial acne. J Cosmet Dermatol. 2018;17(2):203–208.
- Yan J, Liu Y, Cao L, et al. Association between duration of folic acid supplementation during pregnancy and risk of postpartum depression. Nutrients. 2017;9(11). pii: E1206.
- Kamal M, Polat M. Effect of different doses of isotretinoin treatment on the levels of serum homocysteine, vitamin B 12 and folic acid in patients with acne vulgaris: a prospective controlled study. J Pak Med Assoc. 2015;65(9):950–953.
- Balta I, Ekiz O, Ozuguz P, et al. Nutritional anemia in reproductive age women with postadolescent acne. Cutan Ocul Toxicol. 2013;32(3):200–203.
- Mikkelsen K, Stojanovska L, Apostolopoulos V. The effects of vitamin B in depression. Curr Med Chem. 2016;23(38):4317–4337.
- Pan WH, Chang YP, Yeh WT, et al. Co-occurrence of anemia, marginal vitamin B6, and folate status and depressive symptoms in older adults. J Geriatr Psychiatry Neurol. 2012;25(3):170–178.
- Bender A, Hagan KE, Kingston N. The association of folate and depression: a meta-analysis. J Psychiatr Res. 2017;95:9–18.
- Gao L, Liu X, Yu L, et al. Folic acid exerts antidepressant effects by upregulating brain-derived neurotrophic factor and glutamate receptor 1 expression in brain. Neuroreport. 2017;28(16): 1078–1084.
- Green R, Allen LH, Bjørke-Monsen AL, et al. Vitamin B12 deficiency. Nat Rev Dis Primers. 2017;3:17040.
- Stabler SP, Allen RH. Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr. 2004;24: 299–326.
- World Health Organization. Regional strategy on Nutrition 2010–2019 and plan of action. Available at: http://applications.emro.who.int/dsaf/dsa1230.pdf?ua=1. Accessed April 4, 2019.
- Hwalla N, Al Dhaheri AS, Radwan H, et al. The prevalence of micronutrient deficiencies and inadequacies in the middle east and approaches to interventions. Nutrients. 2017; 9(3). pii: 229.
- Gökalp H, Bulur I, Gürer M. Decreased vitamin B12 and folic acid concentrations in acne patients after isotretinoin therapy: a controlled study. Indian J Dermatol. 2014;59(6):630.