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Background:  The two metabolites of vitamin D; serum 25-hydroxyvitamin D 3  (25(OH)D 3 ) and D 2  (25(OH)D 2 ), and their independent roles in mood regulation are unexplored. This study aims to examine 25(OH)D 3  and 25(OH)D 2  and their interplay with depression symptoms. Materials and Methods:  Utilizing data from the U.S. National Health and Nutrition Examination Survey (2007–2011, 2013–2014), a cross-sectional study was conducted. Depression was assessed using the 9-item Patient Health Questionnaire, and those with total score ≥5 were considered as having mild to severe depression symptoms. 25(OH)D 3  and 25(OH)D 2 , the clinical markers of vitamins D 3  and D 2 , were measured. Weighted logistic regressions were utilized to examine the adjusted association between 25(OH)D 3  and depression, and the effect modification of 25(OH)D 2 . Results:  The sample included 11,471 participants aged 20–80 years. Of those, 23.4% reported symptoms of depression, 28.9% had 25(OH)D 3  deficiencies(&lt;20 ng/mL), and 21.5% exhibited presence of 25(OH)D 2 (&gt;0.6 ng/mL). After adjustment, among participants with presence of 25(OH)D 2 , those who had 25(OH)D 3  deficiencies were more likely by 54% to report depression symptoms (OR = 1.54,95%CI:1.14–2.07). In fact, among participants with nearly no 25(OH)D 2  presence, a significant effect estimate between 25(OH)D 3  deficiency and depression symptom was not observed(OR = 1.11,95%CI:0.94–1.31). Conclusions:  Both vitamin D metabolites retain an independent and significant role in mood regulation. The study provides valuable insights on vitamin D 3  and its significant relationship with depression symptoms in the presence of vitamin D 2 . Further research is required to elucidate the distinct mechanisms of these two vitamin D metabolites on depression.

Vitamin D metabolites, D 3 and D 2 , and their independent associations with depression symptoms among adults in the United States