AbstractRelationship between depressive disorder and autonomic nervous system has been already discussed. Reduced emotional regulation is supposed to be associated with prefrontal hypofunction and subcortical hyperactivity. The aim of this study was to determine the effect of vortioxetine on heart rate variability (HRV), a parameter of cardiac autonomic regulation, in depressed hospitalized paediatric patients and assess the clinical effectiveness of the drug in this population.

抑郁症和自主神经系统之间的关系已经被讨论过。情绪调节减少被认为与前额叶功能减退和皮层下活动过度有关。本研究的目的是确定伏替西汀对抑郁症住院儿科患者心率变异性（HRV）的影响，心率变异性是心脏自主调节的一个参数，并评估该药物在该人群中的临床有效性。

We performed repeated polysomnography analyses at admission and after a short treatment in hospital (15.2 days on average) and measured various HRV parameters (RRi, pNN50, RMSSD, LF-HRV, HF-HRV) during wakefulness, N3 and REM sleep stages. Out of 27 study subjects, 67% have improved depression symptoms as well as anxiety and subjective sleep quality after short vortioxetine treatment.

。在27名研究对象中，67%的人在短期伏替西汀治疗后改善了抑郁症状以及焦虑和主观睡眠质量。

We have found a significant decrease in parasympathetic parameters pNN50, RMSSD and HF-HRV during N3 sleep phase, though not exclusively among vortioxetine responders. The anticipated increase in cardiovagal regulation after vortioxetine treatment was not demonstrated in this pilot study, possibly due to the drug’s multimodal mechanism and impact on the nucleus tractus solitarii, particularly its antagonism on 5HT-3 receptors.

我们发现在N3睡眠阶段，副交感神经参数pNN50，RMSSD和HF-HRV显着降低，尽管并非仅在伏替西汀反应者中。vortioxetine治疗后心脏迷走神经调节的预期增加在这项初步研究中没有得到证实，可能是由于该药物的多模式机制和对孤束核的影响，特别是其对5HT-3受体的拮抗作用。

Application of selective drugs could further explain the effect of vortioxetine on HRV in depressed patients..

选择性药物的应用可以进一步解释伏替西汀对抑郁症患者心率变异性的影响。。

IntroductionMastering the capacity to adapt one’s emotional responses to match the specific context, referred to as emotion regulation, stands as a fundamental developmental milestone during early childhood and adolescence. These processes are underpinned by the autonomic nervous system (ANS), a central physiological network responsible for dynamically harmonizing real-time sensory inputs with internal motivational and goal-oriented1.

引言掌握适应情绪反应以适应特定环境的能力，称为情绪调节，是儿童早期和青春期的基本发展里程碑。。

The circuitry between ANS and central nervous system (CNS), shaped early in the course of the life, forms the basis for the adaptive neurovisceral regulation throughout one’s lifetime. Therefore, adolescence contributes significantly to mental well-being rendering this age group notably susceptible to mental disorders.

ANS和中枢神经系统（CNS）之间的电路在生命的早期形成，形成了一生中适应性神经内脏调节的基础。因此，青春期对心理健康有显着贡献，使这个年龄段特别容易患精神障碍。

Indeed, it is estimated that globally 14% of 10–19 aged children and adolescents experience a mental disorder. Major depressive disorder (MDD) is believed to affect approximately 1.1% of individuals in the 10–14-year-old group and 2.8% of those aged 15–192.The autonomic imbalance is associated with a lack of physiological adaptability, dynamic flexibility, and health.

事实上，据估计，全球10-19岁儿童和青少年中有14%患有精神障碍。据信，重度抑郁症（MDD）会影响10-14岁组中约1.1%的人和15-192岁组中2.8%的人。自主神经失衡与缺乏生理适应性，动态灵活性和健康有关。

There are two main theories that support the idea that cardiac vagal regulation indexed by heart rate variability (HRV) is associated with autonomic and emotional regulation. First, polyvagal theory3,4 specifies that the cardiac-linked vagal efferent modulation from the nucleus ambiguus is connected with cranial nerves involved in the emotional expression and vocalization important for emotional and affective regulation in people.

。首先，多迷走神经理论3,4指出，来自疑核的心脏相关迷走神经传出调节与参与情绪表达和发声的颅神经有关，这对人们的情绪和情感调节很重要。

Thus, vagally-mediated HRV index (high frequency, HF-HRV) could be considered as an index of emotional regulation. Further, Thayer and Lane5 reported the significance of cardiac autonomic regulation in the context of neurovisceral int.

因此，迷走神经介导的HRV指数（高频，HF-HRV）可以被认为是情绪调节的指标。此外，Thayer和Lane5报道了心脏自主调节在神经内脏int背景下的重要性。

Table 2 HRV parameters in all subjects, responders, and non-responders before and after short vortioxetine treatment in hospital: RMSSD, HF, LF, RRi, pNN50.Full size tableWhen we compared the HRV parameters between responders and non-responders in both periods, the only parameter pNN50 was significantly higher at admission in non-responders at wake phase (p = 0.0371, d = 0.98).We have not found any significant correlation between HRV parameters at Time 1 and scores of any rating scales (MADRS, HAM-A, AIS, CDI), nor of age.DiscussionThe present study brings new and original insights on autonomic regulation/dysregulation assessed by HRV during sleep in depressed paediatric patients before and after vortioxetine treatment in hospital.

表2所有受试者，应答者和无应答者在医院短期伏替西汀治疗前后的HRV参数：RMSSD，HF，LF，RRi，pNN50。全尺寸表当我们比较两个时期应答者和无应答者之间的HRV参数时，唯一的参数pNN50在清醒期无应答者入院时显着更高（p=0.0371，d=0.98）。我们没有发现时间1的HRV参数与任何评定量表（MADRS，HAM-A，AIS，CDI）的得分之间以及年龄之间存在任何显着相关性。讨论本研究为在医院接受沃替西汀治疗前后抑郁症儿科患者睡眠期间HRV评估的自主调节/失调提供了新的和原始的见解。

To the best of our knowledge, it is a first study describing effects of this antidepressant on HRV. The major findings of this study are following: (1) two thirds of depressed adolescent patients improved their depressive symptoms as well as symptoms of anxiety and insomnia after a short vortioxetine treatment during hospitalization; (2) short vortioxetine treatment significantly decreased parameters pNN50, RMSSD, and HF-HRV during N3 sleep stage in entire group but not in responder group separately.

据我们所知，这是第一项描述这种抗抑郁药对HRV影响的研究。这项研究的主要发现如下：（1）三分之二的抑郁症青少年患者在住院期间接受短期伏替西汀治疗后，改善了抑郁症状以及焦虑和失眠症状；（2） 短伏替西汀治疗显着降低了整个组N3睡眠阶段的参数pNN50，RMSSD和HF-HRV，但分别在应答组中没有。

These major findings and possible mechanisms are discussed below.Applying psychiatric rating scales showed that adolescent patients in our study suffered on average from moderate depression, mild to moderate anxiety and insomnia symptoms such as difficulties with falling asleep, night awakenings, shorter total sleep time, and worsened sleep quality.

下面讨论这些主要发现和可能的机制。应用精神病学评定量表显示，我们研究中的青少年患者平均患有中度抑郁，轻度至中度焦虑和失眠症状，例如入睡困难，夜间觉醒，总睡眠时间缩短以及睡眠质量恶化。

Vortioxetine proved efficacy, significantly improving the clinical status of depressed paediatric patients within a mean hospital treatment duration of 15.2 days, as evidenced by a 50% decrease in MAD.

伏替西汀被证明是有效的，在平均15.2天的住院治疗时间内显着改善了抑郁症儿科患者的临床状况，MAD降低了50%。

Table 3 HRV parameter characteristics.Full size tableStatistical analysesThe data were visualized and statistically analysed by the GraphPad 8.0.1 (GraphPad Prism, San Diego, CA, USA). Shapiro–Wilk test of normality was performed to assess parametric and non-parametric distribution of the data. The effect of short antidepressant treatment determined via psychiatric rating scale scores was analysed by paired t-test (parametric data) or Wilcoxon test (non-parametric data).

表3 HRV参数特征。全尺寸表统计分析数据通过GraphPad 8.0.1（GraphPad Prism，圣地亚哥，加利福尼亚，美国）进行可视化和统计分析。进行Shapiro–Wilk正态性检验以评估数据的参数和非参数分布。通过配对t检验（参数数据）或Wilcoxon检验（非参数数据）分析通过精神病评定量表评分确定的短期抗抑郁药治疗的效果。

Spearman tests were used to assess the correlations between HRV parameters and psychiatric rating scales scores, and age. Mixed ANOVA was used to compare HRV parameters in two times (Time 1, Time 2) and different stages (wakefulness, N3 stage, REM) in three groups (all subjects, responders, non-responders) and then in responders compared to non-responders.

Spearman测试用于评估HRV参数与精神病评定量表评分和年龄之间的相关性。混合方差分析用于比较三组（所有受试者，应答者，无应答者）的两次（时间1，时间2）和不同阶段（清醒，N3阶段，REM）的HRV参数，然后比较应答者与无应答者。

The p-value was corrected post-hoc by Benjamini, Krieger and Yekutieli two-stage step-up method to control false discovery rate. Such P-value ≤ 0.05 was defined as statistically significant. Effect size was calculated by post-hoc comparison of means and standard deviations of two groups using G*Power 3.1.9.4 (Dusseldorf University, Dusseldorf, Germany).Ethical approvalThe study was approved by the Ethics Committee of Jessenius Faculty of Medicine in Martin (EK87/2019) and all the methods were performed in accordance with the Declaration of Helsinki and other relevant guidelines and regulations.Informed consentTo ensure ethical standards are upheld, all participants involved in this study and their parents/legal guardians have been provided with comprehensive information regarding the research objectives, procedures, potential risks, and benefits.

通过Benjamini，Krieger和Yekutieli两阶段升压方法对p值进行事后校正，以控制错误发现率。这种P值≤0.05被定义为具有统计学意义。使用G*Power 3.1.9.4（杜塞尔多夫大学，杜塞尔多夫，德国），通过事后比较两组的平均值和标准偏差来计算效应大小。伦理认可该研究得到马丁杰森尤斯医学院伦理委员会的批准（EK87/2019），所有方法均按照赫尔辛基宣言和其他相关指南和规定进行。。

Furthermore, each participant has voluntarily agreed to participate by providing explicit informed consent.

此外，每个参与者都自愿同意通过提供明确的知情同意书参与。

Data availability

数据可用性

The datasets used and/or analysed during the current study are available from the corresponding author on request.

本研究中使用和/或分析的数据集可应要求从通讯作者处获得。

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Download referencesAcknowledgementsThis work was supported by Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic under grant VEGA 1/0048/24.Author informationAuthor notesThese authors contributed equally: Michaela Krivosova and Peter Hutka.Authors and AffiliationsJessenius Faculty of Medicine in Martin, Biomedical Centre Martin, Comenius University Bratislava, Martin, SlovakiaMichaela Krivosova, Zuzana Visnovcova & Nikola FerencovaJessenius Faculty of Medicine in Martin, Psychiatric Clinic, Comenius University Bratislava, University Hospital Martin, Martin, SlovakiaPeter Hutka, Igor Ondrejka, Dana Funakova, Igor Hrtanek, Zuzana Mlyncekova, Veronika Kovacova, Andrea Macejova, Tomas Kukucka & Ingrid TonhajzerovaDepartment of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University Bratislava, Martin, SlovakiaJuraj MokryDepartment of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University Bratislava, Martin, SlovakiaIngrid TonhajzerovaAuthorsMichaela KrivosovaView author publicationsYou can also search for this author in.

下载参考文献致谢这项工作得到了斯洛伐克共和国教育，科学，研究和体育部科学资助机构的支持，资助VEGA 1/0048/24。作者信息作者注意到这些作者做出了同样的贡献：Michaela Krivosova和Peter Hutka。作者和附属机构杰森尤斯马丁医学院，生物医学中心马丁，夸美纽斯大学布拉迪斯拉发分校，马丁，斯洛伐克克里沃索娃，祖扎纳·维斯诺夫科娃和尼古拉·费伦佐娃·杰森尤斯马丁医学院，夸美纽斯大学布拉迪斯拉发分校精神病诊所，马丁大学医院，马丁，斯洛伐克胡特卡，伊戈尔·昂德雷卡，达纳·福纳科娃，伊戈尔·赫塔内克，祖扎纳·姆林切科娃，维罗尼卡·科瓦科娃，安德里亚·马切娃，托马斯·库库库卡和英格丽德·托尼杰罗娃杰森尤斯药理学系马丁医学，夸美纽斯大学布拉迪斯拉发分校，马丁，斯洛伐克生理学系，杰森尤斯医学院马丁，夸美纽斯大学布拉迪斯拉发分校，马丁，斯洛伐克网格TonhajZerova作者Michaela KrivosovaView作者出版物你也可以在中搜索这位作者。

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PubMed Google ScholarContributionsI.O., I.H. and I.T. designed the study, P.H., I.H., D.F., N.F., Z.M., V.K., A.M. and T.K. performed clinical assessments of patients and polysomnography analyses, Z.V. and M.K. performed statistical analyses, P.H., M.K. and I.T. performed the literature search and wrote the first draft of the paper, I.T., I.O.

PubMed谷歌学术贡献。O、 ，I.H.和I.T.设计了这项研究，P.H.，I.H.，D.F.，N.F.，Z.M.，V.K.，A.M.和T.K.对患者进行了临床评估和多导睡眠图分析，Z.V.和M.K.进行了统计分析，P.H.，M.K.和I.T.进行了文献检索，并撰写了论文的初稿I.T.，I.O。

and J.M. supervised the revision of the paper. All authors contributed to and approved the final version of the manuscript.Corresponding authorCorrespondence to.

J.M.监督了论文的修订。所有作者都参与并批准了稿件的最终版本。对应作者对应。

Igor Ondrejka.Ethics declarations

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Reprints and permissionsAbout this articleCite this articleKrivosova, M., Hutka, P., Ondrejka, I. et al. Vortioxetine’s impact on the autonomic nervous system in depressed children and adolescents: analysis of the heart rate variability.

转载和许可本文引用本文Krivosova，M.，Hutka，P.，Ondrejka，I。等人。Vortioxetine对抑郁症儿童和青少年自主神经系统的影响：心率变异性分析。

Sci Rep 14, 14442 (2024). https://doi.org/10.1038/s41598-024-65278-9Download citationReceived: 30 January 2024Accepted: 18 June 2024Published: 23 June 2024DOI: https://doi.org/10.1038/s41598-024-65278-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

科学报告1414442（2024）。https://doi.org/10.1038/s41598-024-65278-9Download引文收到日期：2024年1月30日接受日期：2024年6月18日发布日期：2024年6月23日OI：https://doi.org/10.1038/s41598-024-65278-9Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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