Immune-neuroendocrine crosstalk in mood and psychotic disorders: A meta-analysis and systematic review

IF 3.7 Q2 IMMUNOLOGY

Brain, behavior, & immunity - health Pub Date : 2025-02-11 DOI:10.1016/j.bbih.2025.100965

Minne Van Den Noortgate , Filip Van Den Eede , Violette Coppens , Erik J. Giltay , Livia De Picker , Manuel Morrens

{"title":"Immune-neuroendocrine crosstalk in mood and psychotic disorders: A meta-analysis and systematic review","authors":"Minne Van Den Noortgate , Filip Van Den Eede , Violette Coppens , Erik J. Giltay , Livia De Picker , Manuel Morrens","doi":"10.1016/j.bbih.2025.100965","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Bidirectional interactions between immune and neuroendocrine mechanisms are involved in mood and psychotic disorders, although individual studies report inconsistent and even contradictory findings on the nature of this crosstalk. Our objective was to perform an up to date systematic review and meta-analysis of the association between hypothalamic-pituitary-adrenal (HPA) axis and immune system functioning in mood and psychotic disorders.</div></div><div><h3>Methods</h3><div>We searched the Pubmed, Web of Science and Embase databases for studies reporting correlations between one or more HPA- and immune markers (IM) in patients with mood or psychotic disorders. We analyzed unchallenged correlations as well as challenge studies investigating the HPA-immune interaction through dexamethasone (DEX) and/or CRH suppression, HPA-mediated challenge of immune cell proliferation, immune challenges, or psychological stressors. Finally, genetic studies focusing on HPA x immune interrelation were evaluated. For meta-analyzable data, three primary outcome measures were defined for immune functioning, namely the pro-inflammatory index (PII) and anti-inflammatory index (AII) for the molecular IM and a composite cellular immune marker score (CCIM) for the cellular IM. Secondary analyses were performed for the individual molecular and cellular IM. Heterogeneity was evaluated with the I<sup>2</sup> statistic. Meta-regression analyses were performed to evaluate the impact of potential covariates (publication year, gender, age, symptom severity) on the primary outcome analyses.</div></div><div><h3>Results</h3><div>93 studies (n = 8226) were included, of which 50 (n = 5649) contained meta-analyzable data. The majority of the included studies (k = 72) investigated major depressive disorder (MDD) patients, nineteen schizophrenia spectrum disorders (SSD) and six bipolar disorder (BD). Under physiological conditions, a poor association was found between cortisol and the PII only in the unmedicated subsample of MDD (k = 8; n = 425; r = .205; z = 2.151; p = .031) and the medicated subsample of SSD (k = 4; n = 152; r = .0.237; z = 2.314; p = .021). No significant correlation was found in MDD between the AII and cortisol (k = 3; n = 1243; r = .005; z = .188; p = .851). Similar results were found for the association between immune cell numbers and cortisol in both MDD (k = 10; n = 773; r = −.005; z = −.113; p = .894) and SSD (k = 4; n = 99; r = .167; z = 1.356; p = .175). A total of 42 studies discussed post-challenge associations between immune alterations and HPA disturbances, of which 12 (n = 389; all MDD) contained meta-analyzable data and 37 entered the systematic review (n = 1783). No post-DEX correlations were found between cortisol and PII (k = 3; n = 105; r = .074; z = .355; p = .722) or CCIM (k = 5; n = 259; r = −.153; z = −1.294; p = .196). However, a significant association was found between post-DEX cortisol/ACTH and PII produced by stimulated blood cells in vitro (k = 3; n = 61; r = .508; z = 4.042; p < .001) as well as for cortisol and CCIM score in MDD after in vitro mitogen stimulation (k = 4; n = 90; r = −.309; z = −2498; p = .012). Following a psychological stressor (k = 6; n = 121), cortisol responses tended to be blunted in all included pathologies, while immune activation was comparable to healthy controls. Genetic studies (k = 7; n = 464) demonstrate altered gene expression of glucocorticoid receptors (GR) in peripheral immune cells in MDD. Heterogeneity over studies tended to be moderate to high.</div></div><div><h3>Discussion</h3><div>The main limitations are the heterogeneity of outcome measures (both HPA and IM) and small sample sizes of the included studies. We conclude that, in physiological conditions, associations between HPA-axis and molecular or cellular IM are absent or poor in both MDD and SSD and psychotropic medication may influence this crosstalk differently in both patient groups. Studies using challenge paradigms in MDD populations did reveal differences in the HPA-immune crosstalk. The normally expected decrease in lymphocytes after DEX distribution tended to be less pronounced in MDD, especially in glucocorticoid-insensitive non-suppressors. It is recommended that future studies should be properly powered and assess HPA functioning using multiple cortisol assessments. Challenge studies are probably more useful than baseline biomarker studies and cellular IM are more informative than molecular IM. It is recommended to broadly assess leucocyte function and, when possible, perform subgroup analyses based on HPA- and/or immune function.</div></div>","PeriodicalId":72454,"journal":{"name":"Brain, behavior, & immunity - health","volume":"44 ","pages":"Article 100965"},"PeriodicalIF":3.7000,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain, behavior, & immunity - health","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666354625000237","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Bidirectional interactions between immune and neuroendocrine mechanisms are involved in mood and psychotic disorders, although individual studies report inconsistent and even contradictory findings on the nature of this crosstalk. Our objective was to perform an up to date systematic review and meta-analysis of the association between hypothalamic-pituitary-adrenal (HPA) axis and immune system functioning in mood and psychotic disorders.

Methods

We searched the Pubmed, Web of Science and Embase databases for studies reporting correlations between one or more HPA- and immune markers (IM) in patients with mood or psychotic disorders. We analyzed unchallenged correlations as well as challenge studies investigating the HPA-immune interaction through dexamethasone (DEX) and/or CRH suppression, HPA-mediated challenge of immune cell proliferation, immune challenges, or psychological stressors. Finally, genetic studies focusing on HPA x immune interrelation were evaluated. For meta-analyzable data, three primary outcome measures were defined for immune functioning, namely the pro-inflammatory index (PII) and anti-inflammatory index (AII) for the molecular IM and a composite cellular immune marker score (CCIM) for the cellular IM. Secondary analyses were performed for the individual molecular and cellular IM. Heterogeneity was evaluated with the I² statistic. Meta-regression analyses were performed to evaluate the impact of potential covariates (publication year, gender, age, symptom severity) on the primary outcome analyses.

Results

93 studies (n = 8226) were included, of which 50 (n = 5649) contained meta-analyzable data. The majority of the included studies (k = 72) investigated major depressive disorder (MDD) patients, nineteen schizophrenia spectrum disorders (SSD) and six bipolar disorder (BD). Under physiological conditions, a poor association was found between cortisol and the PII only in the unmedicated subsample of MDD (k = 8; n = 425; r = .205; z = 2.151; p = .031) and the medicated subsample of SSD (k = 4; n = 152; r = .0.237; z = 2.314; p = .021). No significant correlation was found in MDD between the AII and cortisol (k = 3; n = 1243; r = .005; z = .188; p = .851). Similar results were found for the association between immune cell numbers and cortisol in both MDD (k = 10; n = 773; r = −.005; z = −.113; p = .894) and SSD (k = 4; n = 99; r = .167; z = 1.356; p = .175). A total of 42 studies discussed post-challenge associations between immune alterations and HPA disturbances, of which 12 (n = 389; all MDD) contained meta-analyzable data and 37 entered the systematic review (n = 1783). No post-DEX correlations were found between cortisol and PII (k = 3; n = 105; r = .074; z = .355; p = .722) or CCIM (k = 5; n = 259; r = −.153; z = −1.294; p = .196). However, a significant association was found between post-DEX cortisol/ACTH and PII produced by stimulated blood cells in vitro (k = 3; n = 61; r = .508; z = 4.042; p < .001) as well as for cortisol and CCIM score in MDD after in vitro mitogen stimulation (k = 4; n = 90; r = −.309; z = −2498; p = .012). Following a psychological stressor (k = 6; n = 121), cortisol responses tended to be blunted in all included pathologies, while immune activation was comparable to healthy controls. Genetic studies (k = 7; n = 464) demonstrate altered gene expression of glucocorticoid receptors (GR) in peripheral immune cells in MDD. Heterogeneity over studies tended to be moderate to high.

Discussion

The main limitations are the heterogeneity of outcome measures (both HPA and IM) and small sample sizes of the included studies. We conclude that, in physiological conditions, associations between HPA-axis and molecular or cellular IM are absent or poor in both MDD and SSD and psychotropic medication may influence this crosstalk differently in both patient groups. Studies using challenge paradigms in MDD populations did reveal differences in the HPA-immune crosstalk. The normally expected decrease in lymphocytes after DEX distribution tended to be less pronounced in MDD, especially in glucocorticoid-insensitive non-suppressors. It is recommended that future studies should be properly powered and assess HPA functioning using multiple cortisol assessments. Challenge studies are probably more useful than baseline biomarker studies and cellular IM are more informative than molecular IM. It is recommended to broadly assess leucocyte function and, when possible, perform subgroup analyses based on HPA- and/or immune function.

查看原文本刊更多论文

情绪和精神障碍中的免疫-神经内分泌串扰：荟萃分析和系统回顾

免疫和神经内分泌机制之间的双向相互作用与情绪和精神障碍有关，尽管个别研究对这种相互作用的性质报告不一致甚至相互矛盾的结果。我们的目的是对情绪和精神障碍中下丘脑-垂体-肾上腺（HPA）轴与免疫系统功能之间的关系进行最新的系统回顾和荟萃分析。方法：我们检索Pubmed、Web of Science和Embase数据库，寻找心境或精神障碍患者中一种或多种HPA-和免疫标记物（IM）相关的研究。我们分析了通过地塞米松（DEX）和/或CRH抑制、hpa介导的免疫细胞增殖挑战、免疫挑战或心理压力源调查hpa -免疫相互作用的非挑战相关性和挑战研究。最后，对HPA与免疫相互关系的遗传学研究进行了评价。对于可荟萃分析的数据，定义了免疫功能的三个主要结局指标，即分子IM的促炎指数（PII）和抗炎指数（AII）以及细胞IM的复合细胞免疫标记评分（CCIM）。对个体分子和细胞IM进行二次分析。采用I2统计量评价异质性。进行meta回归分析以评估潜在协变量（出版年份、性别、年龄、症状严重程度）对主要结局分析的影响。结果共纳入93项研究（n = 8226），其中50项（n = 5649）包含元分析数据。大多数纳入的研究（k = 72）调查了重度抑郁症（MDD）患者，19例精神分裂症谱系障碍（SSD）患者和6例双相情感障碍（BD）患者。在生理条件下，只有在未用药的MDD亚样本中，皮质醇和PII之间存在较差的相关性(k = 8；n = 425；r = .205；z = 2.151；p = .031)和SSD药物子样本(k = 4；n = 152；r = 0.237；z = 2.314；p = .021)。在重度抑郁症中，AII与皮质醇无显著相关性(k = 3；n = 1243；r = .005；z = 0.188；p = .851)。在两种MDD中，免疫细胞数量和皮质醇之间的关联也发现了类似的结果(k = 10；n = 773；r =−.005；z =−0.113；p = .894)和SSD (k = 4；n = 99；r = 0.167；z = 1.356；p = .175)。共有42项研究讨论了攻击后免疫改变与HPA紊乱之间的关系，其中12项(n = 389；所有MDD均包含元分析数据，其中37例纳入系统评价（n = 1783）。dex后皮质醇与PII无相关性(k = 3；n = 105；r = 0.074；z = .355；p = .722)或CCIM (k = 5；n = 259；r =−.153；z =−1.294；p = .196)。然而，dex后皮质醇/ACTH与体外刺激血细胞产生的PII之间存在显著关联(k = 3；n = 61；r = .508；z = 4.042；p & lt;.001)以及体外有丝分裂原刺激后MDD患者的皮质醇和CCIM评分(k = 4；n = 90；r =−.309；z =−2498；p = .012)。心理应激源(k = 6；N = 121)，皮质醇反应在所有包括的病理中趋于迟钝，而免疫激活与健康对照相当。基因研究(k = 7；n = 464)表明MDD患者外周免疫细胞中糖皮质激素受体（GR）基因表达改变。研究的异质性往往是中等到高度的。主要的限制是结果测量的异质性（包括HPA和IM）和纳入研究的小样本量。我们的结论是，在生理条件下，hpa -轴与分子或细胞IM之间的关联在重度抑郁症和SSD中都不存在或很差，精神药物可能对两组患者的这种串扰产生不同的影响。在重度抑郁症人群中使用挑战范式的研究确实揭示了hpa -免疫串扰的差异。正常预期的DEX分布后淋巴细胞减少在MDD中不太明显，特别是在糖皮质激素不敏感的非抑制者中。建议未来的研究应适当加强，并使用多种皮质醇评估来评估下丘脑功能。挑战研究可能比基线生物标志物研究更有用，细胞IM比分子IM提供更多信息。建议广泛评估白细胞功能，并在可能的情况下，根据HPA和/或免疫功能进行亚组分析。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊