European Neuropsychopharmacology最新文献

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Efficacy, all-cause discontinuation, and safety of serotonergic psychedelics and MDMA to treat mental disorders: A living systematic review with meta-analysis 5 -羟色胺类致幻剂和MDMA治疗精神障碍的疗效、全因停药和安全性：一项具有荟萃分析的系统回顾

IF 6.7 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology

Pub Date : 2025-12-01 Epub Date: 2025-11-07 DOI: 10.1016/j.euroneuro.2025.09.011

Mikkel Højlund , Helin Y. Kafali , Begüm Kırmızı , Paolo Fusar-Poli , Christoph U. Correll , Samuele Cortese , Michel Sabé , Jess Fiedorowicz , Gayatri Saraf , Josephine Zein , Michael Berk , Muhammad I. Husain , Joshua D. Rosenblat , Ruby Rubaiyat , Kim Corace , Stanley Wong , Simon Hatcher , Mark Kaluzienski , Lakshmi N. Yatham , Andrea Cipriani , Marco Solmi

Serotonergic psychedelics and 3,4-methylendioxtmethamphetamine (MDMA) are promising treatments for mental disorders with a continuously evolving evidence base. We searched Pubmed/Scopus/clinical trial registries up to 08july2025 for double-blind randomized controlled trials (RCTs) testing MDMA or serotonergic psychedelics in patients with mental disorders. Primary outcomes were change in disease-specific symptoms and all-cause discontinuation. Standardized mean differences (SMD) and relative risk (RR) were estimated using random-effects meta-analysis. Risk of bias (RoB) was assessed with Cochrane’s RoB-tool version 2 and certainty of evidence with GRADE. The review is maintained as living systematic review (https://ebipsyche-database.org/). We included 30 RCTs (1480 participants; female=45.8 %; with psychological support=83.3 %; high RoB=83.3 %). In post-traumatic stress disorder (PTSD), MDMA reduced PTSD symptoms compared to any control (k = 11; SMD=-0.85 [-1.09; -0.60]; I²=0 %; GRADE=low). In major depressive disorder (MDD), psilocybin/ayahuasca/LSD reduced depressive symptoms (k = 8; SMD=-0.62 [-0.97; -0.28]; I²=55 %; GRADE=very low). In anxiety disorders, both MDMA and serotonergic psychedelics reduced anxiety symptoms (SMD_MDMA=-1.18 [-2.04; -0.32]; I²=0 %; k = 2; GRADE=low and SMD_serotonergic=-0.88 [-1.70; -0.06]; I²=54 %;k = 5; GRADE=very low). In alcohol use disorder, neither psilocybin nor LSD reduced abstinence rates (k = 6; RR=1.42 [0.89; 2.26]; I²=7 %; GRADE=very low). In attention-deficit hyperactivity disorder (ADHD), LSD did not reduce ADHD symptoms (k = 1; SMD=0.22 [-0.32; 0.76]; GRADE=very low). Moderate certainty in evidence was only found for MDMA on PTSD symptoms when compared to placebo. MDMA/serotonergic psychedelics were not associated with higher risk of all-cause discontinuation (RR_MDMA=0.74 [0.32; 1.72]; RR_serotonergic=0.81 [0.56; 1.15]). Overall, MDMA/serotonergic psychedelics are promising for the treatment of PTSD, MDD, and anxiety disorders with moderate to large effect sizes. Pragmatic trials, long-term, head-to-head trials exploring the role of psychological support, aiming to identify predictors of response, and accounting for expectancy and functional unblinding are needed. Studies addressing these limitations will likely be required for regulatory approval of psychedelic drugs.

5 -羟色胺类致幻剂和3,4-甲基二氧基甲基苯丙胺（MDMA）是治疗精神障碍的有前途的药物，证据基础不断发展。我们检索了截至2025年7月8日的Pubmed/Scopus/临床试验注册库，以进行双盲随机对照试验（rct），测试MDMA或5 -羟色胺能致幻剂对精神障碍患者的影响。主要结局是疾病特异性症状的改变和全因停药。使用随机效应荟萃分析估计标准化平均差异（SMD）和相对风险（RR）。用Cochrane的RoB工具第2版评估偏倚风险（RoB），用GRADE评估证据的确定性。该评价作为活的系统评价（https://ebipsyche-database.org/）进行维护。我们纳入了30项随机对照试验（1480名受试者，女性= 45.8%，心理支持= 83.3%，高RoB= 83.3%）。在创伤后应激障碍（PTSD）中，与任何对照组相比，MDMA减轻了PTSD症状（k = 11； SMD=-0.85 [-1.09; -0.60]; I2= 0%； GRADE=低）。在重度抑郁症（MDD）中，裸盖菇素/死藤水/LSD可减轻抑郁症状（k = 8； SMD=-0.62 [-0.97; -0.28]; I2= 55%； GRADE=非常低）。在焦虑症中，MDMA和5 -羟色胺能致幻剂均能减轻焦虑症状（SMDMDMA=-1.18 [-2.04; -0.32]; I2= 0%;k = 2； GRADE=低，smd5 -羟色胺能=-0.88 [-1.70;-0.06];I2= 54%;k =5； GRADE=极低）。在酒精使用障碍中，裸盖菇素和LSD均未降低戒断率（k = 6； RR=1.42 [0.89; 2.26]; I2= 7%； GRADE=极低）。在注意缺陷多动障碍（ADHD）中，LSD没有减轻ADHD症状（k = 1； SMD=0.22 [-0.32; 0.76]； GRADE=非常低）。与安慰剂相比，只有MDMA对PTSD症状有中度确定性的证据。MDMA/ 5 -羟色胺能致幻剂与全因停药风险无关（RRMDMA=0.74 [0.32; 1.72]; rrmma =0.81[0.56; 1.15]）。总的来说，MDMA/ 5 -羟色胺能致幻剂有望用于治疗创伤后应激障碍，重度抑郁症和焦虑症，具有中等到较大的效果。需要务实的试验，长期的，面对面的试验，探索心理支持的作用，旨在确定反应的预测因素，并考虑期望和功能解盲。解决这些限制的研究可能需要监管部门批准迷幻药。

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引用次数: 0

Cell type-specific methylome-wide association studies of childhood ADHD symptoms 儿童ADHD症状的细胞类型特异性甲基组关联研究

IF 6.7 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology

Pub Date : 2025-12-01 Epub Date: 2025-10-26 DOI: 10.1016/j.euroneuro.2025.09.010

Mandy Meijer , Marieke Klein , Doretta Caramaschi , Shaunna L. Clark , Marta Cosin-Tomas , Nastassja Koen , Xueling Lu , Rosa H. Mulder , Stefan W. Röder , Yining Zhang , Lea Zilich , Mariona Bustamente , Michael Deuschle , Janine F. Felix , Juan Ramos González , Regina Gražulevičiene , Fabian Streit , John Wright , Angel Carracedo , Charlotte A.M. Cecil , Edwin J.C.G. van den Oord

Studying DNA methylation (DNAm) can provide insights into gene-regulatory mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). While most DNAm studies were performed in bulk tissue, this study used statistical deconvolution to identify cell type-specific DNAm profiles, from five major blood cell types, associated with childhood ADHD symptoms. We performed meta-analyses of methylome-wide association studies (MWAS) for ADHD symptoms (age_range=4–16 years) in peripheral blood collected during childhood and in cord blood. The investigated cohorts included seven array-based methylation datasets assaying up to 450 K CpGs from the Pregnancy And Childhood Epigenetics Consortium (N=2 934 peripheral blood; N=2 546 cord blood) and a sequencing-based methylation dataset assaying nearly all 28 million CpGs in blood from the Great Smoky Mountain Study (GSMS; N=583). The meta-analyses resulted in methylome-wide significant (FDR<0.05) ADHD associations in CD8T cells (RPL31P11 and KCNJ5) for peripheral blood, and, in cord blood, in monocytes (PDE6B), CD8T cells (KCNA3 and HAND2), and NK cells (KIFC1). Notably, several significant sites detected in peripheral blood (RPL31P11 and KCNJ5) were also detected in cord blood. Furthermore, extended MWAS of all sites available for GSMS detected 69 and 17 additional CpGs in monocytes and granulocytes, respectively. In this first cell type-specific MWAS for ADHD, we identified DNAm associations for ADHD symptoms; some associations were seen in both peripheral blood and cord blood, suggesting potential susceptibility markers for increased ADHD risk. These findings show that cell type-specific analyses and sequencing-based approaches can increase insights into the epigenetic patterns associated with ADHD symptoms in childhood.

研究DNA甲基化（DNAm）可以深入了解注意力缺陷/多动障碍（ADHD）的基因调控机制。虽然大多数DNAm研究是在大块组织中进行的，但本研究使用统计反褶积来确定与儿童多动症症状相关的五种主要血细胞类型的细胞类型特异性DNAm谱。我们对儿童时期收集的外周血和脐带血中ADHD症状（年龄范围为4-16岁）的甲基组全关联研究（MWAS）进行了荟萃分析。研究队列包括七个基于阵列的甲基化数据集，分析了来自妊娠和儿童表观遗传学协会（N=2 934外周血；N=2 546脐带血）的多达450 K CpGs，以及一个基于测序的甲基化数据集，分析了来自大烟山研究（GSMS； N=583）的几乎所有2800万CpGs血液。荟萃分析结果显示，外周血CD8T细胞（RPL31P11和KCNJ5）、脐带血单核细胞（PDE6B）、CD8T细胞（KCNA3和HAND2）和NK细胞（KIFC1）在甲基组范围内存在显著（FDR<0.05） ADHD关联。值得注意的是，在外周血中检测到的几个重要位点（RPL31P11和KCNJ5）也在脐带血中检测到。此外，GSMS所有可用位点的扩展MWAS分别在单核细胞和粒细胞中检测到69和17个额外的CpGs。在这首个针对ADHD的细胞类型特异性MWAS中，我们确定了DNAm与ADHD症状的关联；在外周血和脐带血中都发现了一些关联，提示ADHD风险增加的潜在易感性标记。这些发现表明，细胞类型特异性分析和基于测序的方法可以增加对与儿童多动症症状相关的表观遗传模式的了解。

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引用次数: 0

Toward rigorous control conditions in trials of digital therapeutics 朝着数字治疗试验中严格的控制条件发展

IF 6.7 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology

Pub Date : 2025-12-01 Epub Date: 2025-10-25 DOI: 10.1016/j.euroneuro.2025.09.013

Nathan T.M. Huneke , Blanca Bolea-Alamañac

引用次数: 0

Response to the letter regarding “Risk of manic switch and suicidal outcomes in bipolar depression treated with esketamine” 对“艾氯胺酮治疗双相抑郁症躁狂转换风险和自杀结果”的回复

IF 6.7 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology

Pub Date : 2025-12-01 Epub Date: 2025-10-25 DOI: 10.1016/j.euroneuro.2025.10.001

Ting-Hui Liu , Jheng-Yan Wu , Po-Yu Huang , Wan-Lin Cheng , Chih-Cheng Lai

引用次数: 0

A call for more robust and interpretable models in predicting treatment-resistant depression 呼吁建立更可靠和可解释的模型来预测难治性抑郁症。

IF 6.7 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology

Pub Date : 2025-12-01 Epub Date: 2025-10-27 DOI: 10.1016/j.euroneuro.2025.09.012

Souichi Oka , Kota Takemura , Yoshiyasu Takefuji

引用次数: 0

Chronic stress and brain kynurenine pathway: addressing unresolved issues with a meta-analytic approach of preclinical studies, translational implication for psychiatric disorders 慢性应激和脑犬尿氨酸通路：用临床前研究的荟萃分析方法解决未解决的问题，对精神疾病的转化意义。

IF 6.7 2区医学 Q1 CLINICAL NEUROLOGY

European Neuropsychopharmacology

Pub Date : 2025-12-01 Epub Date: 2025-11-06 DOI: 10.1016/j.euroneuro.2025.10.005

Andrea de Bartolomeis , Michele Fornaro , Elena Scopetta , Claudio Ricci , Antonella Irano , Giuseppe De Simone , Stefano Comai , Felice Iasevoli , Claudio Caiazza

The kynurenine pathway (KP) has emerged as a key mediator of inflammation and synaptic plasticity, which play a significant role in the pathophysiology of chronic stress (CS). CS, in turn, is a major environmental factor in the development of psychiatric disorders. Despite growing evidence linking the KP to psychiatric disorders, the mechanisms underlying its alterations under CS remain poorly understood. To address this gap, we conducted the first comprehensive meta-analysis of preclinical rodent studies. Our goal was to systematically evaluate, within controlled experimental paradigms: (1) how, to what extent, and in which brain regions CS affects the KP; (2) which neurochemical pathways are most impacted by CS. We searched PubMed/MEDLINE, EMBASE, Scopus for preclinical studies until 06/27/2025. We performed a systematic review and meta-analysis following a pre-determined protocol (PROSPERO:CRD42023459414), considering KP metabolites and enzymes as outcomes (Standardized Mean Difference=SMD). SYRCLE/CAMARADES tools assessed quality and risk-of-bias. 59 studies entered the meta-analyses. CS proved to increase hippocampal and cortical overall concentrations of kynurenine (SMD=1.71,95 %C.I.[0.99,2.42], p < 0.01,I²=91.3 %,k = 23,n = 508; SMD=1.54,95 %C.I.[1.08,2.01],p < 0.01,I²=57.77 %,k = 16,n = 247), as well as kynurenine/tryptophan ratio and quinolinic acid. KYNA concentrations decreased in the hippocampus and cortex. KP enzyme expression/activity, including Indoleamine-2,3-Dioxygenase, Tryptophan-2,3-Dioxygenase, Kynurenine-3-Monoxygenase, increased. These findings support a shift of tryptophan metabolism towards the KP following CS. Particularly, the increase in neurotoxic quinolinic acid (NMDAR-agonist) and decrease in KYNA (NMDA-antagonist) may disrupt the neuroprotection/excitotoxic neuronal balance, influencing neuroplasticity. The KP may play a key role in the pathophysiology of CS-associated behaviors, and could serve to highlight potential targets for novel therapeutic strategies, specifically for treatment resistance.

犬尿氨酸通路（KP）是炎症和突触可塑性的关键介质，在慢性应激（CS）的病理生理中起着重要作用。反过来，CS是精神疾病发展的主要环境因素。尽管越来越多的证据将KP与精神疾病联系起来，但在CS下其改变的机制仍然知之甚少。为了解决这一差距，我们对临床前啮齿动物研究进行了首次全面的荟萃分析。我们的目标是在受控的实验范式中系统地评估：(1)CS如何、在多大程度上以及在哪些脑区影响KP；(2) CS对哪些神经化学通路影响最大。我们检索了PubMed/MEDLINE， EMBASE， Scopus的临床前研究，直到2025年6月27日。我们按照预先确定的方案（PROSPERO:CRD42023459414）进行了系统回顾和荟萃分析，将KP代谢物和酶作为结果（标准化平均差=SMD）。sycle /CAMARADES工具评估了质量和偏倚风险。59项研究纳入了荟萃分析。CS可提高海马和皮质犬尿氨酸总浓度（SMD=1.71, 95% C.I.[0.99,2.42], p < 0.01,I2= 91.3%,k = 23,n = 508； SMD=1.54, 95% C.I.[1.08,2.01],p < 0.01,I2= 57.77%,k = 16,n = 247），以及犬尿氨酸/色氨酸比值和喹啉酸。海马和皮质KYNA浓度下降。KP酶（吲哚胺-2,3-双加氧酶、色氨酸-2,3-双加氧酶、犬尿氨酸-3-单加氧酶）的表达/活性增加。这些发现支持了CS后色氨酸代谢向KP的转变。特别是，神经毒性喹啉酸（nmda -激动剂）的增加和KYNA （nmda -拮抗剂）的减少可能会破坏神经保护/兴奋毒性神经元平衡，影响神经可塑性。KP可能在cs相关行为的病理生理中发挥关键作用，并可能为新的治疗策略（特别是治疗耐药性）提供潜在靶点。

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