To the Editor: Depression is a major contributor to the global burden of disease and disability, posing a critical public health challenge. Meta-analyses have demonstrated that vitamin D supplementation significantly reduces major depressive symptoms (MDS).1 However, recent large-scale randomised controlled trials (RCTs)2-4 have yielded conflicting evidence, indicating that vitamin D supplementation may not necessarily reduce MDS risk. This discrepancy may be attributed to variations in baseline serum 25-hydroxyvitamin D (25(OH)D) levels, insufficiently characterised dose–response relationships and uncertain optimal 25(OH)D thresholds. Further studies are urgently needed to elucidate the dose–response relationships between serum 25(OH)D levels and depression risk, which will inform evidence-based intervention strategies for optimising vitamin D supplementation protocols. Therefore, our study aimed to determine the optimal serum 25(OH)D thresholds through a comprehensive dose–response analysis with MDS and to elucidate the distinct physiological roles of 25(OH)D2 and 25(OH)D3. We investigated the dose–response relationships between serum 25(OH)D metabolites and MDS using data from seven cycles (2007–2018, 2021–2023) of the National Health and Nutrition Examination Survey (NHANES). Notably, 25(OH)D biomarker data for 2019–2020 have not been released. The study was approved by the National Center for Health Statistics Research Ethics Review Board in accordance with the principles of the Declaration of Helsinki. All participants provided written informed consent. Exclusion criteria were as follows: (1) missing 9-item Patient Health Questionnaire (PHQ-9) data; (2) age 67.0 nmol/L, restricting 25(OH)D2 to 63.0 nmol/L. These results advocate for a precision medicine approach to depression prevention, where baseline vitamin D status informs tailored supplementation rather than universal dosing. Individuals with severe deficiency ( 67.0 nmol/L, 25(OH)D3 > 63.0 nmol/L, 25(OH)D2 < 12.9 nmol/L) provides an evidence-based framework for precision supplementation in mental health. These findings suggest that personalised vitamin D3 supplementation, guided by baseline 25(OH)D levels and targeting optimal thresholds, may offer a promising, cost-effective strategy for depression prevention. This precision nutrition approach could potentially reconcile the longstanding discrepancy between observational studies and previous RCTs. Conceptualisation and formal analysis: Qinghua Fan and Rongtian Xu. Funding acquisition: Haibo Wang. Methodology: Rongtian Xu, Yi Guo and Zhongjian Liu. Software and visualisation: Zhongjian Liu and Yi Guo. Writing—original draft: Rongtian Xu and Qinghua Fan. Writing—review and editing: Haibo Wang. Critical revision and final approval: all authors. This study was supported by the Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project (2021ZD0200600). The authors declare no conflicts of interest. Qinghua Fan is a research assistant at the Clinical Research Institute, Institute of Advanced Clinical Medicine, Peking University in China (2024–present). He obtained a master's degree in preventive medicine from Guangxi Medical University in China (2021–2024). He has been involved in several clinical cohorts of depression during his work. His main research interests include neuroimaging and biomarker studies in patients with major depressive disorder, with particular emphasis on understanding the neural mechanisms underlying depression and developing precision medicine approaches for treatment. He is also interested in investigating the relationship between brain connectivity patterns and treatment response in depression, aiming to identify biomarkers that can predict therapeutic outcomes and guide personalised treatment strategies. All articles used in this study are publicly available data, with the relevant studies cited. This paper analyses existing, publicly available data. Any additional information required to reanalyse the data reported in this report is available from the lead contact upon request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Fan et al. (Sun,) studied this question.