Divergent lymphocyte associations with depression severity and case status in first-episode, drug-naive adolescents: A multicenter study

doi:10.5498/wjp.119439

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World Journal of Psychiatry

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2220-3206

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Psychiatry. Jul 19, 2026; 16(7): 119439
Published online Jul 19, 2026. doi: 10.5498/wjp.119439

Divergent lymphocyte associations with depression severity and case status in first-episode, drug-naive adolescents: A multicenter study

Xi-Wang Fan, Jia-Zhe Hou, Yi-Zhe Wang, Ming-Lin Gao, Ying Shen, Dai Jian, Qin Zhou, Jing Yang, Hui Zhao, Li-Juan Zhang

Xi-Wang Fan, Yi-Zhe Wang, Ming-Lin Gao, Hui Zhao, Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai 200124, China

Jia-Zhe Hou, Jing Yang, Li-Juan Zhang, Health Management Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai 201613, China

Ying Shen, Psychosomatic Medicine, The Third People’s Hospital of Ganzhou, Ganzhou 341000, Jiangxi Province, China

Dai Jian, Department of Clinical Psychology, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Third People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi Zhuang Autonomous Region, China

Qin Zhou, The Affiliated Xuzhou Eastern Hospital of Xuzhou Medical University, Xuzhou Eastern People’s Hospital, Xuzhou 221004, Jiangsu Province, China

Co-first authors: Xi-Wang Fan and Jia-Zhe Hou.

Author contributions: Fan XW contributed to methodology, formal analysis; Fan XW, Hou JZ, Wang YZ, Gao ML, and Yang J contributed to manuscript writing - review and editing; Fan XW, Hou JZ, Wang YZ, Yang J, Zhao H, and Zhang LJ participated in manuscript writing - original draft; Hou JZ was involved in data sorting, analysis, visualization; Wang YZ participated in validation; Shen Y contributed to investigation and resources; Shen Y, Jian D, and Zhou Q contributed to data curation; Jian D and Zhou Q were involved in investigation; Zhao H contributed to and supervised the study; Zhang LJ contributed to study conceptualization, supervision, project administration, and funding acquisition; Fan XW and Hou JZ contributed equally to this manuscript and are co-first authors.

AI contribution statement: During manuscript preparation, relevant language-editing tools were used solely for English-language polishing and grammatical refinement. The scientific content of the manuscript, including the study conception and design, data collection and analysis, interpretation of results, and formulation of conclusions, was completed independently by the authors and was not generated by artificial intelligence. These tools were used only to improve linguistic accuracy, clarity, and readability. They were not used for data processing, statistical analysis, result generation, or the development of academic content. Artificial intelligence tools had no role in the conception or design of the study, interpretation of findings, or any scholarly decision-making. No figures, images, or other visual materials in this manuscript were generated by artificial intelligence. We would like to emphasize that all scientific aspects of the study were conducted independently by the authors, and artificial intelligence tools were used strictly for language refinement purposes.

Supported by National Natural Science Foundation of China, No. 81872720; and the Shanghai Municipal Health Commission, No. 2023ZZ02027; and the National Clinical Key Specialty Construction Project of China, No. Z155080000004.

Institutional review board statement: The study protocol was reviewed and approved by the Ethics Committee of the Shanghai Pudong New Area Mental Health Center, Approval No.[2022] Research Review No. 011. All research activities were conducted in strict accordance with the principles of the Declaration of Helsinki and complied with relevant national and local regulatory standards to ensure the ethical conduct of research involving human participants.

Informed consent statement: Written informed consent was obtained from all participants aged 18 years or above. For participants younger than 18 years, written informed consent was obtained from a parent or legal guardian, and a written agreement for study participation was obtained from the adolescent when applicable.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.

Data sharing statement: The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.

Corresponding author: Li-Juan Zhang, PhD, Health Management Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, No. 50 Chifeng Road, Yangpu District, Shanghai 201613, China. zhangxiaoyi@tongji.edu.cn

Received: January 29, 2026
Revised: February 22, 2026
Accepted: March 24, 2026
Published online: July 19, 2026
Processing time: 148 Days and 18.6 Hours

Abstract

BACKGROUND

Adolescent major depressive disorder (MDD) imposes an increasingly severe global health burden. Current diagnosis relies predominantly on subjective symptom reporting. Adolescents exhibit a unique immunobiological landscape, characterized by immune signatures that differ from those of adults. This feature may enable development of an immunopsychiatric framework for adolescent depression.

AIM

To investigate whether routinely measured peripheral immune parameters could both identify depression and reflect its severity in treatment-naive adolescents.

METHODS

We employed a two-stage, multicenter design. In stage I, a cross-sectional sample of 2115 first-episode, drug-naive adolescents with MDD was recruited from three regional centers in China. Associations between peripheral immune parameters and derived ratios with depression severity were assessed by the Self-Rating Depression Scale, with sex-stratified analyses. In stage II, a case-control study enrolled 41 adolescents with MDD and 41 controls. Multivariable logistic regression and receiver operating characteristic analyses were performed to evaluate the discriminatory capacity of candidate immune indicators.

RESULTS

Compared with healthy peers, adolescents with MDD had significantly lower lymphocyte counts [odds ratio (OR) = 0.27, 95% confidence interval (CI): 0.13-0.57] and lymphocyte-to-monocyte ratio (LMR; OR = 0.72, 95%CI: 0.56-0.92). Paradoxically, within the MDD group, higher lymphocyte count (OR = 1.10, 95%CI: 1.01-1.22) and LMR (OR = 1.06, 95%CI: 1.01-1.13) were independently associated with greater depression severity, an effect most accentuated in female participants (OR = 1.17, 95%CI: 1.01-1.35). receiver operating characteristic analyses confirmed moderate discriminative accuracy for lymphocyte count [area under the curve (AUC) = 0.76, 95%CI: 0.66-0.87] and LMR (AUC = 0.70, 95%CI: 0.59-0.81). A composite model integrating age, sex, and key immune parameters achieved good discrimination (bootstrap-corrected AUC = 0.79, 95%CI: 0.73-0.82).

CONCLUSION

Our findings reveal a bidirectional immunological pattern in adolescent MDD: Reduced lymphocyte count supports diagnostic identification, while elevated levels correlate with greater illness severity. These results support a stage-dependent immunopsychiatric model and lend support to precision mental health strategies in youth.

Keywords: Adolescent depression; Lymphocyte count; Lymphocyte-to-monocyte ratio; Peripheral immunity; Severity; Multicenter study

Core Tip: This two-stage multicenter study reveals a divergent immunopurified in first-episode, drug-naive adolescents with major depressive disorder. While patients exhibited significantly lower lymphocyte counts and lymphocyte-to-monocyte ratios than healthy controls, higher levels of these markers paradoxically correlated with greater disease severity, particularly in females. A composite model integrating these indices demonstrated robust diagnostic discrimination (area under the curve = 0.82). These findings support a stage-dependent immunopsychiatric paradigm, suggesting that routine peripheral immune metrics offer a practical, objective tool for identifying major depressive disorder and stratifying severity in youth.