舍曲林对首发重度抑郁症青少年患者血清炎症因子的影响研究

Effect of Sertraline on Serum Cytokine Levels in Adolescents With First-Episode Major Depressive Disorder

娇娇向 , ¹ 素洪 , ¹ 柳毅冉 , ² 琪曾 , ² 裔婷孔 , ¹ 晨钰张 , ¹ 婧廖 , ² and 利况 ^1, ^Δ

娇娇向

重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

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素洪

重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

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柳毅冉

重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

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琪曾

重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

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裔婷孔

重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

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晨钰张

重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

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婧廖

重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

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利况

重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China 重庆医科大学附属第一医院精神科（重庆 400016）, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China 重庆医科大学附属大学城医院心理卫生中心（重庆 401331）, Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China

娇娇向: moc.361@559joaijgnaiX ; 利况: moc.361@8030ilgnauk

E-mail： moc.361@8030ilgnauk HC: healthy control; MDD: major depressive disorder; BMI: body mass index.Age/yr.15.35±0.8415.08±1.33−1.2850.202Sex/case (%)0.1090.742　Male15 (27.30)15 (24.60)　Female40 (72.70)46 (75.40)Education/year9.39±1.209.39±1.680.2460.806BMI/(kg/m ² )20.12±2.7420.99±3.661.4760.143Smoking history/case (%)0.0111.000　Yes2 (3.60)2 (3.30)　No53 (96.40)59 (96.70)Alcohol consumption/case (%)0.0351.000　Yes4 (7.30)5 (8.20)　No51 (92.70)56 (91.80)Family history/case (%)6.7170.014　Yes0 (0)7 (11.50)　No55 (100)54 (88.50)

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2.2. MDD青少年治疗前后与健康青少年细胞因子水平的差异

如表2 所示，基线时（治疗前）MDD组的IL-1β和IL-6水平高于HC组（ P 均<0.0001），而TNF-α水平低于HC组（ P =0.006）。用药8周后，MDD组IL-1β、IL-6水平均较治疗前下降，而TNF-α水平较治疗前升高。MDD组治疗后IL-1β、TNF-α恢复到HC组水平（ P >0.05），但IL-6仍高于HC组（ P <0.05）。如表3 所示，MDD组经8周治疗后，HAMD-17、CD-RISC总分、坚韧、相信直觉及控制得分均升高，而积极接受和精神影响得分无显著变化。

表 2

Comparison of cytokine levels between the HC group and the MDD group before and after treatment

MDD患者治疗前后与健康对照血清炎症因子比较

Index	MDD group ( n =61)		HC group ( n =55)
Index	Before treatment	After treatment	HC group ( n =55)
IL: interleukin; TNF: tumor necrosis factor; the other abbreviations are explained in the note to Table 1. ^* P <0.05, vs. HC group; ^# P <0.05, vs. after treatment in MDD group.
IL-1β	55.76±11.43 ^{*, #}	45.19±8.49	42.49±9.92
IL-6	30.87±3.25 ^{*, #}	29.06±5.87 ^*	26.15±7.93
TNF-α	44.97±11.19 ^#	48.78±7.96	49.37±7.23

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表 3

Comparison of changes in depression levels before and after treatment in 61 MDD patients

61例MDD患者治疗前后抑郁程度变化比较

Index	Before treatment	After treatment
HAMD-17: 17-item Hamilton Depression Scale; CD-RISC: Connor-Davidson Resilience Scale; PC: perceived competence; TT: trust and tolerance; ACC: acceptance; CTRL: control; SPR: spirituality.
HAMD-17	23.43±3.30	13.41±6.20	12.055	<0.001
CD-RISC	30.02±15.15	37.44±19.89	−3.556	0.001
PC	9.04±6.23	11.43±7.52	−2.684	0.010
TT	7.24±4.51	9.30±5.39	−3.399	0.001
ACC	7.22±3.35	8.11±4.41	−1.776	0.082
CTRL	3.39±2.31	4.57±2.98	−3.162	0.003
SPR	3.59±2.07	4.04±2.04	−1.454	0.152

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根据HAMD-17评分的变化，61例参与者被分为27例有应答者（44.3%）和34例无应答者（55.7%）。如表4 所示，应答者和无应答者之间的基线期炎症因子无显著差异。

表 4

Comparison of baseline cytokine levels between responders and nonresponders to MDD treatment

MDD患者应答组与无应答组的基线血清炎症因子比较

Index	Responders ( n =27)	Nonresponders ( n =34)
MDD: major depressive disorder; IL: interleukin; TNF: tumor necrosis factor.
IL-1β	56.17±13.99	55.44±9.13	0.234	0.816
IL-6	30.84±3.67	30.89±2.93	−0.070	0.945
TNF-α	44.87±10.92	45.06±11.58	−0.064	0.949

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2.3. 炎症因子水平与抑郁严重程度的相关性

如表5 所示，基线IL-1β、IL-6水平均与基线时HAMD-17评分呈中等强度正相关，而与基线时CD-RISC总分及其坚韧、相信直觉、积极接受和控制4个因子评分负相关。基线TNF-α水平仅与基线HAMD-17评分弱相关。基线IL-6水平与治疗后的CD-RISC总分及其相信直觉、积极接受、控制3个因子评分弱相关。治疗后的IL-6水平与治疗后的CD-RISC总分及其坚韧、相信直觉2个因子评分弱相关，而治疗前后的IL-1β、TNF-α水平与治疗前后的HAMD-17评分和CD-RISC总分及其5个因子评分均无相关性。

表 5

Correlation between cytokine levels and the severity of depression ( r )

炎症因子水平与抑郁严重程度的相关性分析（ r ）

Index	IL-1β ₀	IL-6 ₀	TNF-α ₀	IL-1β _{8 w}	IL-6 _{8 w}	TNF-α _{8 w}
IL: interleukin; TNF: tumor necrosis factor; the other abbreviations are explained in the note to Table 3. ^** P <0.001, ^* P <0.05.
HAMD-17 ₀	0.536 ^**	0.414 ^**	−0.194 ^*
CD-RISC ₀	−0.413 ^**	−0.329 ^**	0.137
PC ₀	−0.416 ^**	−0.339 ^**	0.167
TT ₀	−0.345 ^**	−0.254 ^**	0.130
ACC ₀	−0.303 ^**	−0.286 ^**	0.131
CTRL ₀	−0.347 ^**	−0.315 ^**	0.055
SPR ₀	−0.171	0.009	−0.030
HAMD-17 _{8 w}	0.101	0.094	−0.008	0.005	−0.009	0.246
CD-RISC _{8 w}	−0.123	−0.346 ^**	−0.025	0.030	0.306 ^*	−0.239
PC _{8 w}	−0.130	−0.259	−0.037	−0.046	0.321 ^*	−0.220
TT _{8 w}	−0.058	−0.299 ^*	−0.072	0.076	0.270 ^*	−0.198
ACC _{8 w}	−0.108	−0.334 ^*	0.071	−0.023	0.244	−0.206
CTRL _{8 w}	−0.104	−0.286 ^*	−0.090	0.068	0.205	−0.232
SPR _{8 w}	−0.109	−0.244	0.019	−0.039	0.179	−0.137

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如表6 所示，在逐步线性回归分析模型中，基线IL-1β、TNF-α水平和基线期积极接受评分是基线期HAMD-17评分的独立因素，而基线期间IL-1β、TNF-α水平对治疗后的HAMD-17评分影响无统计学意义。

表 6

Stepwise linear regression of the HAMD-17 scores

HAMD-17的逐步线性回归

Dependent variable	Predictive variable
B : regression coefficient; SE : standard error; β : standard regression coefficient; the other abbreviations are explained in the note to Table 3.
HAMD-17 ₀	IL-1β ₀	0.465	0.064	0.503	7.308	<0.001
	TNF-α ₀	−0.198	0.082	−0.161	−2.426	0.017
	ACC ₀	−1.069	0.194	−0.382	−5.505	<0.001
HAMD-17 _{8 w}	TT ₀	−0.485	0.172	−0.356	−2.823	0.007

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3. 讨论

本研究通过对比首发重度抑郁症青少年患者与健康青少年的血清炎症因子水平来识别预测舍曲林治疗青少年重度抑郁症的疗效的有效因子。

在本研究中通过提取MDD患者和健康对照组的静脉血，检测血清炎症标志物IL-1β、IL-6和TNF-α。结果发现青少年MDD患者血清中IL-1β和IL-6水平高于健康青少年，而基线期TNF-α水平低于健康青少年。既往许多研究表明，IL-1β和IL-6在 MDD患者中升高，并且和MDD的症状和治疗反应存在密切关系 ^{[

16

-

18

]} ，这与本研究结果一致。在8周治疗后，MDD组的IL-1β和IL-6水平均下降，且青少年MDD患者治疗后IL-1β水平与健康青少年相比无明显差异，而TNF-α水平在治疗后有升高的趋势。有啮齿类动物研究提示舍曲林可以与小胶质细胞中的TNF-α和TNF受体1结合，阻断TNF触发的NF-κB信号通路及其下游促炎细胞因子的合成，能够有效抑制小胶质细胞产生TNF-α和自由基一氧化氮，从而实现舍曲林的抗炎症机制 ^{[

19

]} 。PÉREZ-SÁNCHEZ等 ^{[

20

]} 的研究显示，青少年MDD患者在基线期的IL-6和TNF-α水平高于健康对照组，且在为期8周的治疗观察中仅在第4周出现浓度下降。一项关注儿童和青少年MDD的荟萃分析显示，MDD患者外周TNF-α水平高于健康对照组，但差异没有统计学意义 ^{[

21

]} 。GABBAY等 ^{[

22

]} 的研究显示，伴有自杀行为的青少年MDD患者的外周TNF-α水平低于不伴自杀行为的MDD青少年。在一项成人首发MDD患者血浆细胞因子的研究中显示，IL-1β、IL-6和TNF-α在4周抗抑郁治疗后显著下降 ^{[

23

]} 。这些结果的异质性可能来源于MDD青少年与成年患者的区别，以及是否为首发未用药患者的差异，在青少年MDD的外周血促炎因子中，IL-1β、IL-6可能更多地参与了青少年MDD的发生发展NG等 ^{[

24

]} 的荟萃分析显示，患抑郁症老年人的IL-6高于对照组。BUSPAVANICH等 ^{[

25

]} 的一项在成人中的研究显示，抑郁发病较快的患者的血清中IL-2、IL-4、IL-6、IL-10、TNF-α和IFN-γ水平相较发病较慢的患者显著降低。本研究与成年MDD研究结果一致，青少年MDD也存在免疫系统功能失调。一项荟萃分析显示，应答者与无应答者的MDD患者在基线期的IL-1β、IL-6和TNF-α水平无明显差异，这与本研究的结果一致 ^{[

26

]} ，在青少年MDD治疗中，治疗前后的外周血炎症水平存在差异，舍曲林改变了青少年MDD患者体内炎症水平，但基线期炎症因子水平与疗效无显著相关性，这可能与纳入检测的炎症因子较少、样本量小有关。本研究结果为青少年抑郁症患者的体内的异常细胞因子水平和免疫功能失衡提供了更多的证据，舍曲林已被证明可以缓解抑郁，并在免疫激活状态下恢复正常的细胞免疫功能，这进一步提示IL-1β、IL-6、TNF-α参与了青少年抑郁症的发病机制，但遗憾的是本研究未能检测到能够预测疗效的炎症因子。免疫系统与年龄的变化密切相关，受到内分泌、神经、消化、心血管等生理系统变化的影响 ^{[

27

]} ，因此在MDD青少年免疫功能失调也可能反映了其他健康问题（如肥胖）潜在风险的增加，对青少年重度抑郁症患者的免疫功能随访以及躯体健康疾病监测存在必要性。

MDD患者经过8周治疗后，HAMD-17呈现下降趋势，而CD-RISC及其坚韧、相信直觉、控制3个因子评分呈现上升趋势，治疗后评分与治疗前评分相比差异有统计学意义。本研究发现治疗前IL-1β、IL-6水平与基线HAMD-17评分正相关，而与CD-RISC及其坚韧、相信直觉、积极接受和控制4个因子评分负相关，其中治疗前后的IL-6水平与治疗前后的CD-RISC及其相信直觉因子评分的相关系数检验均有统计学意义，可见IL-6水平与心理弹性和应激应对能力相关，提升应激时的心理应对能力可能有助于抑郁症的恢复。

本研究结合了横断面和纵向研究，对MDD组和对照组进行了年龄、性别、受教育程度的匹配，且纳入试验组的患者均为首次发病且未经治疗的青少年患者，控制了药物对基线期炎症水平的影响。本研究控制了潜在的混杂偏倚，排除了有其他影响情绪的精神疾病、急慢性炎症、使用免疫调节剂的患者。本研究仍存在一些不足之处，MDD亚组样本量相对较小，需要进一步研究来评估反应者和非反应者炎症水平差异。本研究主要涉及临床试验，炎症也不能单独解释抑郁症的发病，其作用机制需要进一步研究。

本研究显示，IL-1β和IL-6的升高可能是青少年抑郁症发病的生物标志物，舍曲林治疗可以降低IL-1β、IL-6水平，基线IL-1β、IL-6水平与舍曲林抗抑郁疗效无关。青少年MDD患者治疗后的应激应对能力和心理弹性水平较前提高，治疗前后的IL-6水平与治疗前后的CD-RISC及其相信直觉因子评分均为弱相关，这提示IL-6具有作为抑郁症疗效的分子生物标志物的进一步研究前景，但在本研究中尚不足以支持作为预测抗抑郁疗效的指标。

*　　　　*　　　　*

利益冲突 所有作者均声明不存在利益冲突

Funding Statement

国家自然科学基金面上项目（No. 81971286）资助

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Articles from Journal of Sichuan University (Medical Sciences) are provided here courtesy of Editorial Board of Journal of Sichuan University (Medical Sciences)

舍曲林对首发重度抑郁症青少年患者血清炎症因子的影响研究

Effect of Sertraline on Serum Cytokine Levels in Adolescents With First-Episode Major Depressive Disorder

娇娇 向

素 洪

柳毅 冉

琪 曾

裔婷 孔

晨钰 张

婧 廖

利 况

2.2. MDD青少年治疗前后与健康青少年细胞因子水平的差异

表 2

表 3

表 4

2.3. 炎症因子水平与抑郁严重程度的相关性

表 5

表 6

3. 讨论

Funding Statement

References

娇娇向

素洪

柳毅冉

琪曾

裔婷孔

晨钰张

婧廖

利况