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Objective <p>While inflammation is implicated in pathophysiology of major depressive disorder (MDD), the effect of interleukin (IL) profile in first-episode, drug-naïve MDD (FEDN-MDD) patients remains unclear. This study aimed to delineate the plasma IL signature, establish a diagnostic biomarker panel, and characterize cytokine-symptom relationships in FEDN-MDD.</p> Methods <p>This cross-sectional study included 170 participants, comprising 101 FEDN-MDD patients and 69 healthy controls (HCs). Depression and anxiety severity were assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17) and Hamilton Anxiety Rating Scale (HAMA-14), respectively. Fasting plasma samples were collected, and concentrations of 13 types of interleukins (IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p70), IL-13, IL-15, IL-17) were measured using Luminex xMAP technology. LASSO regression with 10-fold cross-validation was employed for biomarker selection, and polynomial regression was used to model nonlinear associations.</p> Results <p>After demographic adjustment, 12 of 13 ILs were significantly elevated in MDD versus HCs (all <i>p</i> &lt; 0.001), with IL-9 showing the largest effect size (partial η²=0.544). LASSO regression identified a 3-cytokine panel (IL-7, IL-9, IL-17) with outstanding diagnostic accuracy (AUC = 0.958, sensitivity = 88.1%, specificity = 89.9%). Crucially, IL-9 exhibited an inverted U-shaped relationship with symptom severity (all quadratic <i>p</i> &lt; 0.05), where both depression (HAMD-17) and anxiety (HAMA-14) severity peaked at IL-9 concentrations near 1000 pg/mL (95% Bootstrap CIs: ~800–1070 pg/mL).</p> Conclusion <p>Plasma IL-9 is a pivotal mediator in FEDN-MDD, exhibiting a unique concentration-symptom dynamic and driving a high-accuracy diagnostic triad. This highlights its promise as a candidate target for mechanistic investigation and a potential tool for precision psychiatry.</p>

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Nonlinear associations of plasma IL-9 with depression and anxiety symptoms in first-episode, drug-naïve major depressive disorder

  • 期刊论文

  • 发表日期：

    2026年4月4日

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  • Yan Zhou,
  • Zhuojun Han,
  • Ning Yang,
  • Meijuan Li,
  • Mengxin Xie,
  • Changlin Zhang,
  • Shuo Wang,
  • Ying Gao,
  • Jie Li

摘要

Objective

While inflammation is implicated in pathophysiology of major depressive disorder (MDD), the effect of interleukin (IL) profile in first-episode, drug-naïve MDD (FEDN-MDD) patients remains unclear. This study aimed to delineate the plasma IL signature, establish a diagnostic biomarker panel, and characterize cytokine-symptom relationships in FEDN-MDD.

Methods

This cross-sectional study included 170 participants, comprising 101 FEDN-MDD patients and 69 healthy controls (HCs). Depression and anxiety severity were assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17) and Hamilton Anxiety Rating Scale (HAMA-14), respectively. Fasting plasma samples were collected, and concentrations of 13 types of interleukins (IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p70), IL-13, IL-15, IL-17) were measured using Luminex xMAP technology. LASSO regression with 10-fold cross-validation was employed for biomarker selection, and polynomial regression was used to model nonlinear associations.

Results

After demographic adjustment, 12 of 13 ILs were significantly elevated in MDD versus HCs (all p < 0.001), with IL-9 showing the largest effect size (partial η²=0.544). LASSO regression identified a 3-cytokine panel (IL-7, IL-9, IL-17) with outstanding diagnostic accuracy (AUC = 0.958, sensitivity = 88.1%, specificity = 89.9%). Crucially, IL-9 exhibited an inverted U-shaped relationship with symptom severity (all quadratic p < 0.05), where both depression (HAMD-17) and anxiety (HAMA-14) severity peaked at IL-9 concentrations near 1000 pg/mL (95% Bootstrap CIs: ~800–1070 pg/mL).

Conclusion

Plasma IL-9 is a pivotal mediator in FEDN-MDD, exhibiting a unique concentration-symptom dynamic and driving a high-accuracy diagnostic triad. This highlights its promise as a candidate target for mechanistic investigation and a potential tool for precision psychiatry.