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Effectiveness of Disease-Modifying Treatment on Spinal Cord Lesion Formation in Relapse-Onset Multiple Sclerosis: An MSBase Registry Study. 疾病调整治疗对复发型多发性硬化症脊髓病变形成的影响:MSBase 登记研究
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-06 DOI: 10.1007/s40263-024-01115-x
Daniel Kreiter, Tomas Kalincik, Raymond Hupperts, Francesco Patti, Daniele Spitaleri, Matteo Foschi, Andrea Surcinelli, Davide Maimone, Bassem Yamout, Samia J Khoury, Jeannette Lechner-Scott, Serkan Ozakbas, Oliver Gerlach

Background: Spinal cord lesions in multiple sclerosis (MS) have considerable impact on disability. High-efficacy disease-modifying treatments (hDMTs) are associated with greater reduction of relapses and new brain lesions compared to low-efficacy treatments (lDMTs). Knowledge on the impact of DMTs on cord lesion formation is limited as these outcome measures were not included in MS treatment trials. This study aims to investigate whether hDMTs reduce the formation of cord lesions more effectively than lDMTs.

Methods: Patients with relapse-onset MS, a cord magnetic resonance imaging (MRI) within 6 months before/after initiation of their first DMT and ≥1 cord MRI at follow-up (interval > 6 months) were extracted from the MSBase registry (ACTRN12605000455662). Patients treated with hDMTs ≥90% or lDMTs ≥90% of follow-up duration were considered the hDMT and lDMT groups, respectively. Matching was performed using propensity scores. Cox proportional hazards models were used to estimate the hazards of new cord lesions, brain lesions and relapses.

Results: Ninety-four and 783 satisfied hDMT and lDMT group criteria, respectively. Seventy-seven hDMT patients were matched to 184 lDMT patients. In the hDMT group there was no evidence of reduction of new cord lesions (hazard ratio [HR] 0.99 [95% CI 0.51, 1.92], p = 0.97), while there were fewer new brain lesions (HR 0.22 [95% CI 0.10, 0.49], p < 0.001) and fewer relapses (HR 0.45 [95% CI 0.28, 0.72], p = 0.004).

Conclusion: A potential discrepancy exists in the effect of hDMTs over lDMTs in preventing spinal cord lesions versus brain lesions and relapses. While hDMTs provided a significant reduction for the latter when compared to lDMTs, there was no significant reduction in new spinal cord lesions.

背景:多发性硬化症(MS)的脊髓病变对残疾有很大影响。与低效治疗(lDMTs)相比,高效改变病情治疗(hDMTs)能更有效地减少复发和脑部新病变。由于多发性硬化症治疗试验未包括这些结果测量,因此有关DMTs对脊髓病变形成的影响的知识十分有限。本研究旨在探讨hDMTs是否比lDMTs更有效地减少脊髓病变的形成:方法:从 MSBase 注册表(ACTRN12605000455662)中抽取复发多发性硬化症患者,这些患者在首次使用 DMT 之前/之后的 6 个月内进行过一次脊髓磁共振成像(MRI),并且在随访期间(间隔时间大于 6 个月)进行过≥1 次脊髓磁共振成像。随访时间内接受hDMT治疗≥90%或接受lDMT治疗≥90%的患者分别被视为hDMT组和lDMT组。采用倾向评分进行匹配。采用 Cox 比例危险度模型估算新的脊髓病变、脑部病变和复发的危险度:分别有94人和783人符合hDMT组和lDMT组标准。77名hDMT患者与184名lDMT患者进行了配对。在 hDMT 组中,没有证据表明新的脊髓病变减少(危险比 [HR] 0.99 [95% CI 0.51, 1.92],p = 0.97),而新的脑部病变减少(HR 0.22 [95% CI 0.10, 0.49],p < 0.001),复发减少(HR 0.45 [95% CI 0.28, 0.72],p = 0.004):在预防脊髓病变与脑损伤和复发方面,hDMTs与lDMTs的效果可能存在差异。虽然 hDMTs 比 lDMTs 能显著减少脑损伤和复发,但却不能显著减少新的脊髓病变。
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引用次数: 0
Current Perspectives on the Clinical Research and Medicalization of Psychedelic Drugs for Addiction Treatments: Safety, Efficacy, Limitations and Challenges. 关于迷幻药物用于成瘾治疗的临床研究和医学化的当前视角:安全性、有效性、局限性和挑战。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-20 DOI: 10.1007/s40263-024-01101-3
Anton Gomez-Escolar, Daniel Folch-Sanchez, Joanna Stefaniuk, Zoe Swithenbank, Andreia Nisa, Fleur Braddick, Nazish Idrees Chaudhary, Pim B van der Meer, Albert Batalla

Mental health disorders and substance use disorders (SUDs) in particular, contribute greatly to the global burden of disease. Psychedelics, including entactogens and dissociative substances, are currently being explored for the treatment of SUDs, yet with less empirical clinical evidence than for other mental health disorders, such as depression or post-traumatic stress disorder (PTSD). In this narrative review, we discuss the current clinical research evidence, therapeutic potential and safety of psilocybin, lysergic acid diethylamide (LSD), ketamine, 3,4-methylenedioxymethamphetamine (MDMA) and ibogaine, particularly in the context of the SUD treatment. Our aim was to provide a balanced overview of the current research and findings on potential benefits and harms of psychedelics in clinical settings for SUD treatment. We highlight the need for more clinical research in this particular treatment area and point out some limitations and challenges to be addressed in future research.

精神疾病,尤其是药物使用障碍(SUDs),是全球疾病负担的重要组成部分。目前,人们正在探索将迷幻剂(包括接触诱导剂和分离物质)用于治疗 SUD,但与抑郁症或创伤后应激障碍(PTSD)等其他精神疾病相比,其临床实践证据较少。在这篇叙述性综述中,我们讨论了迷幻药、麦角酰二乙胺(LSD)、氯胺酮、3,4-亚甲二氧基甲基苯丙胺(MDMA)和伊博卡因目前的临床研究证据、治疗潜力和安全性,尤其是在治疗 SUD 方面。我们的目的是均衡地概述目前关于迷幻药在治疗精神分裂症的临床环境中的潜在益处和危害的研究和发现。我们强调了在这一特定治疗领域开展更多临床研究的必要性,并指出了未来研究中需要解决的一些局限性和挑战。
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引用次数: 0
New and Emerging Drug and Gene Therapies for Friedreich Ataxia. 治疗弗里德里希共济失调的新兴药物和基因疗法。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-08 DOI: 10.1007/s40263-024-01113-z
Varlli Scott, Martin B Delatycki, Geneieve Tai, Louise A Corben

The life shortening nature of Friedreich Ataxia (FRDA) demands the search for therapies that can delay, stop or reverse its relentless trajectory. This review provides a contemporary position of drug and gene therapies for FRDA currently in phase 1 clinical trials and beyond. Despite significant scientific advances in the specificity of both compounds and targets developed and investigated, challenges remain for the advancement of treatments in a limited recruitment population. Currently therapies focus on reducing oxidative stress and improving mitochondrial function, modulating frataxin controlled metabolic pathways and gene replacement and editing. Approval of omaveloxolone, the first treatment for individuals with FRDA aged 16 years and over, has created much excitement for both those living with FRDA and those that care for them. The process of approval of omaveloxolone by the US Food and Drug Administration highlighted the importance of sensitive outcome measures and the significant role of data from natural history studies.

弗里德里希共济失调症(FRDA)会缩短患者的寿命,因此需要寻找能够延缓、阻止或逆转其无情发展轨迹的疗法。本综述介绍了目前处于一期临床试验及以后阶段的弗里德里希共济失调(FRDA)药物和基因疗法的现状。尽管已开发和研究的化合物和靶点在特异性方面取得了重大科学进步,但在有限的招募人群中推进治疗仍面临挑战。目前的疗法主要集中在减少氧化应激和改善线粒体功能、调节 frataxin 控制的代谢途径以及基因替换和编辑。omaveloxolone是首个针对16岁及以上FRDA患者的治疗药物,它的批准令FRDA患者和照顾他们的人倍感兴奋。美国食品和药物管理局批准奥马韦洛酮的过程强调了敏感结果测量的重要性以及自然史研究数据的重要作用。
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引用次数: 0
Assessment of Bone Mineral Density Over 1 Year in a Cross-Sectional Cohort of Migraine Patients Receiving Anti-CGRP Monoclonal Antibodies. 评估接受抗 CGRP 单克隆抗体治疗的偏头痛患者横断面队列一年内的骨矿物质密度。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-22 DOI: 10.1007/s40263-024-01104-0
Davide Para, Chiara Camponovo, Gianna Carla Riccitelli, Giulia Mallucci, Paolo Maino, Camilla Mondini Trissino da Lodi, Demurtas Saudina, Pierpaolo Trimboli, Claudio Gobbi, Chiara Zecca

Background: Calcitonin gene-related peptide (CGRP), implicated in migraine pain, also possesses bone anabolic properties, which leads to the possibility that monoclonal antibodies targeting CGRP (anti-CGRPs) might increase the risk of bone density abnormalities.

Objective: The objective of this study was to explore bone mineral density abnormalities in a cohort of migraine patients treated with anti-CGRPs.

Methods: This was a single-center, cross-sectional, cohort study including migraine patients who underwent a densitometry assessment during anti-CGRP treatment. We assessed the frequency of osteopenia or osteoporosis (OSTEO+ status), defined as a bone mineral density T-score of -1 to -2.5, and <-2.5 standard deviations from the young female adult mean, respectively. Additionally, the association of OSTEO+ status with anti-CGRP treatment duration and primary osteoporosis' risk factors was investigated using logistic regression models.

Results: Data from 51 patients (43 female, mean age 46 ± 13.9 years) were evaluated. The mean duration of anti-CGRP treatment was 15.7 (±11.8) months. Twenty-seven patients (53%) were OSTEO+ (n = 22 osteopenia; n = 5 osteoporosis). In the final model, menopause [odds ratio 11.641 (95% confidence interval 1.486-91.197), p = 0.019] and anti-seizure drug use [odds ratio 12.825 (95% confidence interval 1.162-141.569), p = 0.037] were associated with OSTEO+ status.

Conclusions: In our cohort of migraine patients, no evidence of an association between anti-CGRP treatment duration and an increasing risk of bone mineral density abnormalities was found. However, these findings are preliminary and necessitate further longitudinal research with larger cohorts and extended follow-up to be validated.

背景:降钙素基因相关肽(CGRP)与偏头痛有关,它也具有骨质同化特性,这导致靶向CGRP的单克隆抗体(抗CGRPs)可能会增加骨密度异常的风险:本研究旨在探讨接受抗CGRPs治疗的偏头痛患者队列中的骨矿物质密度异常情况:这是一项单中心、横断面队列研究,研究对象包括在接受抗CGRP治疗期间接受骨密度测量评估的偏头痛患者。我们评估了骨质疏松症或骨质疏松症(OSTEO+状态)的频率,骨质疏松症或骨质疏松症(OSTEO+状态)的定义是骨矿密度T-score为-1至-2.5:评估了 51 名患者(43 名女性,平均年龄为 46 ± 13.9 岁)的数据。抗 CGRP 治疗的平均持续时间为 15.7(±11.8)个月。27 名患者(53%)为 OSTEO+(n = 22 例骨质疏松症;n = 5 例骨质疏松症)。在最终模型中,绝经[几率比 11.641(95% 置信区间 1.486-91.197),p = 0.019]和服用抗癫痫药物[几率比 12.825(95% 置信区间 1.162-141.569),p = 0.037]与 OSTEO+ 状态相关:在我们的偏头痛患者队列中,没有发现抗CGRP治疗持续时间与骨矿物质密度异常风险增加之间存在关联的证据。然而,这些研究结果只是初步的,还需要更大规模的队列和更长时间的随访来验证。
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引用次数: 0
Incident Benzodiazepine and Z-Drug Use and Subsequent Risk of Serious Infections. 苯二氮卓类药物和 Z 类药物的使用与随后的严重感染风险。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-01 DOI: 10.1007/s40263-024-01108-w
Xinchen Wang, Kayoko Isomura, Paul Lichtenstein, Ralf Kuja-Halkola, Brian M D'Onofrio, Isabell Brikell, Patrick D Quinn, Nanbo Zhu, Nitya Jayaram-Lindström, Zheng Chang, David Mataix-Cols, Anna Sidorchuk
<p><strong>Background and objectives: </strong>Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections.</p><p><strong>Methods: </strong>This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose-response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), > 20 DDDs ≤ 65, and > 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients.</p><p><strong>Results: </strong>In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9% female), the crude incidence rate of any serious infections in BZDR recipients and matched nonrecipients during 1-year follow-up was 4.18 [95% confidence intervals (CI) 4.13-4.23] and 1.86 (95% CI 1.83-1.89) per 100 person-years, respectively. After controlling for demographic, socioeconomic, clinical, and pharmacological confounders, BZDR use was associated with 83% relative increase in risk of any infections [hazard ratio (HR) 1.83, 95% CI 1.79-1.89]. The risk remained increased, although attenuated, in the co-twin cohort (HR 1.55, 95% CI 1.23-1.97) and active comparator cohort (HR 1.33, 95% CI 1.30-1.35). The observed risks were similar across different types of initial BZDRs and across individual BZDRs, and the risks increased with age at BZDR initiation. We also observed a dose-response association between cumulative BZDR dosage and risk of serious infections.</p><p><strong>Conclusions: </strong>BZDR initiation was associated with increased risks of serious infections, even when considering unmeasured familial confounding and confoundi
背景和目的:动物研究表明,苯并二氮杂卓和相关 Z 类药物 (BZDR) 的使用与免疫功能障碍之间存在联系。人类的相应证据有限,且主要集中在肺炎方面。本研究旨在评估使用苯二氮卓类药物与随后发生严重感染之间的关系:这项基于瑞典登记册的研究包括一个人口统计学匹配队列、一个同卵双胞对照队列和一个积极的参照队列。在 2007 年之前未使用过 BZDR 的 7362979 名 65 岁以下人群中,有 713896 名在 2007 年至 2019 年期间使用过任何 BZDR 的 BZDR 受试者与 713896 名未使用过 BZDR 的普通人群进行了 1:1 匹配;9197 名 BZDR 受试者与其 9298 名未接触过 BZDR 的同卵双胞胎/同卵多胞胎进行了比较;434900 名 BZDR 受试者与 428074 名选择性血清素再摄取抑制剂 (SSRI) 受试者进行了比较。研究结果通过全国患者登记册中首次住院或专科门诊严重感染的诊断,或死因登记册中作为根本原因记录的任何感染导致的死亡来确定。Cox比例危害回归模型已被拟合,并控制了多种混杂因素,包括家族混杂因素和适应症混杂因素。为了研究可能存在的剂量-反应关系,对每位BZDR接受者在随访期间的BZDR累积配药剂量进行了估算,并将其建模为时变暴露,剂量类别为三等分[≤20定义日剂量(DDDs),>20DDDs≤65,>65DDDs]。与人口统计学上匹配的非受试者相比,评估了BZDR受试者在每个累积BZDR剂量类别中的感染风险:在人口统计学匹配队列(使用 BZDR 的平均年龄为 42.8 岁,56.9% 为女性)中,BZDR 受试者和匹配的非受试者在 1 年随访期间任何严重感染的粗发病率分别为每 100 人年 4.18 例 [95% 置信区间 (CI) 4.13-4.23] 和 1.86 例 (95% CI 1.83-1.89)。在控制了人口、社会经济、临床和药物等混杂因素后,使用 BZDR 与任何感染风险相对增加 83% 有关[危险比 (HR) 1.83,95% CI 1.79-1.89]。在同卵双胞队列(HR 1.55,95% CI 1.23-1.97)和积极的比较队列(HR 1.33,95% CI 1.30-1.35)中,风险仍然增加,但有所减弱。在不同类型的初始 BZDR 和不同的 BZDR 中观察到的风险相似,风险随开始服用 BZDR 时的年龄而增加。我们还观察到,BZDR累积剂量与严重感染风险之间存在剂量反应关系:结论:即使考虑到未测量的家族混杂因素和适应症混杂因素,BZDR 的使用也与严重感染风险的增加有关。然而,BZDR 影响免疫功能的确切途径仍不清楚。需要进一步研究探索使用BZDR与严重感染之间关联的神经生物学机制,以便为需要使用BZDR的患者制定更安全的治疗策略。
{"title":"Incident Benzodiazepine and Z-Drug Use and Subsequent Risk of Serious Infections.","authors":"Xinchen Wang, Kayoko Isomura, Paul Lichtenstein, Ralf Kuja-Halkola, Brian M D'Onofrio, Isabell Brikell, Patrick D Quinn, Nanbo Zhu, Nitya Jayaram-Lindström, Zheng Chang, David Mataix-Cols, Anna Sidorchuk","doi":"10.1007/s40263-024-01108-w","DOIUrl":"10.1007/s40263-024-01108-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose-response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), &gt; 20 DDDs ≤ 65, and &gt; 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9% female), the crude incidence rate of any serious infections in BZDR recipients and matched nonrecipients during 1-year follow-up was 4.18 [95% confidence intervals (CI) 4.13-4.23] and 1.86 (95% CI 1.83-1.89) per 100 person-years, respectively. After controlling for demographic, socioeconomic, clinical, and pharmacological confounders, BZDR use was associated with 83% relative increase in risk of any infections [hazard ratio (HR) 1.83, 95% CI 1.79-1.89]. The risk remained increased, although attenuated, in the co-twin cohort (HR 1.55, 95% CI 1.23-1.97) and active comparator cohort (HR 1.33, 95% CI 1.30-1.35). The observed risks were similar across different types of initial BZDRs and across individual BZDRs, and the risks increased with age at BZDR initiation. We also observed a dose-response association between cumulative BZDR dosage and risk of serious infections.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;BZDR initiation was associated with increased risks of serious infections, even when considering unmeasured familial confounding and confoundi","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"827-838"},"PeriodicalIF":7.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effects of Trazodone on Sleep: A Systematic Review and Meta-analysis. 曲唑酮对睡眠的影响:系统回顾与元分析》。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-09 DOI: 10.1007/s40263-024-01110-2
Maria Kokkali, Elisavet Pinioti, Andreas S Lappas, Nikolaos Christodoulou, Myrto T Samara

Background and objectives: Sleep problems and insomnia are common, challenging to treat, and transcend specific diagnoses. Although trazodone is a popular choice, robust meta-analytic evidence is lacking. This systematic review and meta-analysis investigates the efficacy and safety of trazodone for sleep disturbances, reflecting recent updates in insomnia diagnosis and treatment.

Methods: We searched Medline, Embase, APA PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) up to 1 May 2024, for Randomized Controlled Trials (RCTs) comparing trazodone with placebo and reporting sleep-related outcomes. The minimum pharmacotherapy duration was 5 days. Included were all RCTs regardless of blinding (open-label or single- or double-blind), while quasi-randomized studies were excluded. The Cochrane Risk of Bias Tool for Randomized Trials assessed bias. Analyses used a random-effects model on an intention-to-treat (ITT) basis. Risk ratio (RR) was used for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes. When different units or scales were used, Hedge's adjusted g standardized mean difference (SMD) was calculated. Subgroup and preplanned sensitivity analyses explored heterogeneity and evaluated findings' strength and consistency.

Results: In total, 44 RCTs with 3935 participants were included. Trazodone did not significantly impact subjective total sleep time (TST) [WMD = 0.73 min, 95% confidence interval (CI) - 24.62; 26.07, p = 0.96] but improved sleep quality (SQ) (SMD = - 0.58, 95% CI - 0.87; - 0.28, p < 0.01) and secondary outcomes. These included the number of nocturnal awakenings (SMD = - 0.57, 95% CI - 0.85; - 0.30], p < 0.01), nocturnal time awake after sleep onset (WMD = - 13.47 min, 95% CI - 23.09; - 3.86], p < 0.01), objective TST by polysomnography (WMD = 27.98 min, 95% CI 4.02; 51.95, p = 0.02), and sleep efficiency (WMD = 3.32, 95% CI 0.53; 1.57, p = 0.02). Tolerability issues included more dropouts owing to adverse effects (RR = 2.30, 95% CI 1.45; 3.64, p < 0.01), any sleep-related adverse effects (RR = 3.67, 95% CI 1.07; 12.47, p = 0.04), more adverse effects in general (RR = 1.18, 95% CI 1.03; 1.33, p = 0.02), and more sleep-related adverse effects (RR = 4.31, 95% CI 2.29; 8.13, p < 0.01).

Conclusion: Trazodone extends total sleep time but does not affect perceived sleep duration. It may improve sleep quality and continuity but has minor effects on sleep latency, efficiency, and daytime impairment. Trazodone is associated with adverse effects, necessitating a careful risk-benefit assessment. Limited data restrict generalizability, underscoring the need for more research.

Registration: PROSPERO registration number,CRD42022383121.

背景和目的:睡眠问题和失眠症很常见,治疗起来具有挑战性,并且超越了特定的诊断。虽然曲唑酮(Trazodone)是一种常用药物,但目前尚缺乏可靠的荟萃分析证据。本系统综述和荟萃分析调查了曲唑酮治疗睡眠障碍的有效性和安全性,反映了失眠诊断和治疗的最新进展:我们检索了Medline、Embase、APA PsycINFO、Cochrane对照试验中央注册中心(CENTRAL)、ClinicalTrials.gov和世界卫生组织(WHO)国际临床试验注册平台(ICTRP)截至2024年5月1日的随机对照试验(RCT),比较了曲唑酮与安慰剂,并报告了睡眠相关结果。最短药物治疗时间为 5 天。纳入的所有 RCT 均不考虑盲法(开放标签、单盲或双盲),但排除了准随机研究。科克伦随机试验偏倚风险工具对偏倚进行了评估。分析采用随机效应模型,以意向治疗(ITT)为基础。二分结果采用风险比(RR),连续结果采用加权平均差(WMD)。如果使用不同的单位或量表,则计算 Hedge's 调整 g 标准化平均差 (SMD)。亚组分析和预先计划的敏感性分析探讨了异质性,并评估了研究结果的强度和一致性:结果:共纳入 44 项 RCT,3935 名参与者。曲唑酮对主观总睡眠时间(TST)没有明显影响[WMD = 0.73 min,95% 置信区间(CI)- 24.62; 26.07,p = 0.96],但改善了睡眠质量(SQ)(SMD = - 0.58,95% CI - 0.87; - 0.28,p 结论:曲唑酮能延长患者的总睡眠时间:曲唑酮可延长总睡眠时间,但不会影响感知睡眠时间。曲唑酮可改善睡眠质量和连续性,但对睡眠潜伏期、睡眠效率和日间障碍的影响较小。曲唑酮会产生不良反应,因此有必要进行谨慎的风险效益评估。有限的数据限制了该药物的普遍性,因此需要进行更多的研究:注册:PROSPERO 注册号:CRD42022383121。
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引用次数: 0
Antiseizure Medications and Sudden Unexpected Death in Epilepsy: An Updated Review. 抗癫痫药物与癫痫患者的意外猝死:最新综述。
IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-07 DOI: 10.1007/s40263-024-01112-0
Anemoon T Bosch, Josemir W Sander, Roland D Thijs

Sudden unexpected death in epilepsy (SUDEP) is responsible for most epilepsy-related deaths. It is mainly related to unwitnessed nocturnal convulsions, either focal to bilateral or generalised tonic-clonic seizures (TCS). Targeted preventive strategies are currently lacking as underlying mechanisms are largely unknown. Antiseizure medications (ASMs) modulate SUDEP risk through seizure reduction, but it is yet undetermined whether individual ASMs or other medications could also influence the internal SUDEP cascade. Seizure detection devices (SDD) may offer an alternative strategy by preventing TCS from being unwitnessed. Here, we critically evaluated the current evidence on the influence of ASMs, non-epilepsy concomitant drugs and SDD on SUDEP occurrence. We found no robust evidence for the effect of starting ASMs on SUDEP beyond TCS control, but we found some indications of a protective effect for polytherapy. We found no signs that specific ASMs exert a risk for SUDEP. One study suggested a possible protective effect of levetiracetam requiring further investigation. Only a few small studies addressed the association between non-epilepsy concomitant drugs and SUDEP, with no consistent effect for psychotropic medications and one more extensive study suggesting a lower risk among statin users. We only found indirect evidence indicating a protective effect for enhancing nocturnal supervision without explicitly addressing the impact of SDD on SUDEP occurrence. Further work is needed to explore the potential of ASMs and other interventions to modulate SUDEP risk, and they should accurately account for TCS frequency, polypharmacy and markers of non-adherence.

癫痫意外猝死(SUDEP)是大多数癫痫相关死亡的原因。它主要与未经目击的夜间惊厥(从局灶到双侧或全身强直阵挛发作(TCS))有关。由于基本机制尚不清楚,目前还缺乏有针对性的预防策略。抗癫痫药物(ASMs)通过减少癫痫发作来调节 SUDEP 风险,但个别 ASMs 或其他药物是否也会影响 SUDEP 的内部级联尚未确定。癫痫发作检测设备(SDD)可提供一种替代策略,防止三联征(TCS)在无人目击的情况下发生。在此,我们对 ASM、非癫痫伴随药物和 SDD 对 SUDEP 发生的影响的现有证据进行了严格评估。我们没有发现任何有力的证据表明,开始使用 ASMs 会对 TCS 控制以外的 SUDEP 产生影响,但我们发现一些迹象表明,多药治疗具有保护作用。我们没有发现任何迹象表明特定的 ASM 会对 SUDEP 产生风险。一项研究表明,左乙拉西坦可能具有保护作用,这需要进一步调查。只有少数几项小型研究探讨了非癫痫并发症药物与 SUDEP 之间的关联,其中精神药物没有一致的影响,而一项更广泛的研究表明他汀类药物使用者的风险较低。我们只发现了间接证据表明加强夜间监护具有保护作用,而没有明确探讨 SDD 对 SUDEP 发生的影响。我们需要进一步开展工作,探索 ASM 和其他干预措施在调节 SUDEP 风险方面的潜力,并应准确考虑 TCS 频率、多重用药情况和不依从性指标。
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引用次数: 0
Early Disease-Modifying Treatments for Presymptomatic Multiple Sclerosis 针对无症状多发性硬化症的早期疾病调节疗法
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-16 DOI: 10.1007/s40263-024-01117-9
Burcu Zeydan, Christina J. Azevedo, Naila Makhani, Mikael Cohen, Melih Tutuncu, Eric Thouvenot, Aksel Siva, Darin T. Okuda, Orhun H. Kantarci, Christine Lebrun-Frenay

Radiologically isolated syndrome (RIS) is the earliest stage in the disease continuum of multiple sclerosis (MS). RIS is discovered incidentally in individuals who are asymptomatic but have typical lesions in the brain and/or spinal cord suggestive of demyelination. The 2009 and revised 2023 RIS criteria were developed for diagnosis. Presymptomatic individuals who fulfill the 2009 RIS criteria by having 3–4 of 4 dissemination in space McDonald 2005 MS criteria are still diagnosed with RIS using the revised 2023 RIS criteria. In presymptomatic individuals who do not fulfill the 2009 RIS criteria, the revised 2023 RIS criteria target to secure an accurate and timely diagnosis: In addition to (a) having one lesion in two of four locations (periventricular, juxtacortical/cortical, infratentorial, spinal cord), (b) two of three features (spinal cord lesion, cerebrospinal fluid (CSF)-restricted oligoclonal bands, and new T2 or gadolinium-enhancing lesion) should be fulfilled. Among laboratory biomarkers, CSF kappa-free light chain can also increase diagnostic accuracy. Once the diagnosis is confirmed, the established risk factors, including demographics, imaging, and laboratory biomarkers, should be evaluated for symptomatic MS transition and prognosis. Younger age, male sex, increased neurofilament-light chain, CSF abnormality, and the presence of infratentorial, spinal cord, or gadolinium-enhancing lesions on imaging are the main risk factors for transition to symptomatic MS. Two randomized clinical trials showed significant efficacy of disease-modifying treatments in delaying or preventing the development of the first clinical event in RIS. However, because some individuals remain as RIS, it is crucial to identify the individuals with a higher number of risk factors to optimize disease outcomes by early intervention while minimizing adverse events. Discussing each RIS case with an expert MS team is recommended because there is still a lack of clinical guidelines to improve care, counseling, and surveillance.

放射学孤立综合征(RIS)是多发性硬化症(MS)疾病连续过程中的最早阶段。RIS是在无症状但大脑和/或脊髓有典型病变提示脱髓鞘的患者中偶然发现的。2009 年和修订后的 2023 年 RIS 诊断标准已经制定。符合 2009 年 RIS 标准的无症状患者,如果在麦当劳 2005 MS 标准的 4 个播散点中有 3-4 个播散点,则仍可根据修订后的 2023 年 RIS 标准诊断为 RIS。对于不符合2009年RIS标准的无症状患者,修订后的2023年RIS标准旨在确保准确及时的诊断:除了(a)在四个部位(脑室周围、皮质/皮质并区、脑室下、脊髓)中的两个部位有一个病变外,(b)还应符合三个特征(脊髓病变、脑脊液(CSF)限制性寡克隆带、新的T2或钆增强病变)中的两个特征。在实验室生物标志物中,脑脊液无卡帕轻链也能提高诊断的准确性。一旦确诊,应评估已有的危险因素,包括人口统计学、影像学和实验室生物标志物,以确定无症状多发性硬化的转归和预后。年龄较小、男性、神经丝光链增加、脑脊液异常以及影像学上存在幕下、脊髓或钆增强病变是向无症状多发性硬化症转变的主要危险因素。两项随机临床试验显示,改变病情的治疗在延迟或预防 RIS 首次临床事件的发生方面具有显著疗效。然而,由于部分患者仍为 RIS,因此必须识别出具有较多风险因素的患者,以便通过早期干预优化疾病预后,同时最大限度地减少不良事件的发生。建议与 MS 专家团队讨论每个 RIS 病例,因为目前仍缺乏临床指南来改善护理、咨询和监测。
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引用次数: 0
Current Landscape of NTRK Inhibition for Pediatric CNS Tumors NTRK抑制剂治疗小儿中枢神经系统肿瘤的现状
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-15 DOI: 10.1007/s40263-024-01121-z
Daniel C. Moreira, Margit Mikkelsen, Giles W. Robinson

Over the last decade, as molecular platforms have permitted the characterization of the genomic landscape of pediatric central nervous system (CNS) tumors, pediatric neuro-oncology has dramatically transformed. NTRK fusions are oncogenic driver alterations that have been found in a multitude of tumor types, including pediatric CNS tumors. In recent years, NTRK inhibitors have emerged as a promising class of targeted therapies for pediatric CNS tumors with NTRK gene fusions. The use of larotrectinib and entrectinib in the relapsed setting for pediatric CNS tumors has resulted in rapid and robust responses in an important fraction of patients. These agents are well tolerated, although close to 20% of patients have spontaneous bone fractures. Given the existing data for patients with relapsed disease, clinical trials using NTRK inhibitors in the upfront setting is the next natural progression of efficacy testing and many are currently underway. There are still several challenges that need to be addressed to optimize the use of NTRK inhibitors and identify the patients with NTRK fusion-positive CNS tumors who are most likely to benefit from them. As these agents are more broadly used, resistance will become a more pervasive issue and strategies will need to be determined for this scenario. This article summarizes the current status of NTRK inhibitors for pediatric CNS tumors and discusses the opportunities and challenges of their expanding use in the future.

过去十年间,随着分子平台对小儿中枢神经系统(CNS)肿瘤基因组特征的描述,小儿神经肿瘤学发生了巨大变化。NTRK 融合是一种致癌驱动基因改变,已在包括小儿中枢神经系统肿瘤在内的多种肿瘤类型中发现。近年来,NTRK抑制剂已成为治疗NTRK基因融合的小儿中枢神经系统肿瘤的一类前景广阔的靶向疗法。拉罗替尼(larotrectinib)和恩替替尼(entrectinib)用于治疗复发的小儿中枢神经系统肿瘤,已使相当一部分患者产生了快速、稳健的反应。这些药物的耐受性良好,但有近 20% 的患者出现自发性骨折。鉴于复发患者的现有数据,在前期使用 NTRK 抑制剂进行临床试验是疗效测试的下一个自然进展,目前许多临床试验正在进行中。要优化 NTRK 抑制剂的使用并确定最有可能从中获益的 NTRK 融合阳性中枢神经系统肿瘤患者,仍有一些难题需要解决。随着这些药物得到更广泛的应用,耐药性将成为一个更加普遍的问题,因此需要针对这种情况确定相应的策略。本文总结了NTRK抑制剂治疗小儿中枢神经系统肿瘤的现状,并讨论了未来扩大使用的机遇和挑战。
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引用次数: 0
Rett Syndrome: The Emerging Landscape of Treatment Strategies 雷特综合征:新出现的治疗策略
IF 6 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-09 DOI: 10.1007/s40263-024-01106-y
Alan K. Percy, Amitha Ananth, Jeffrey L. Neul
<p>Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (<i>MECP2</i>) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation—IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype–genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal <i>MECP2</i> gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editi
雷特综合征(RTT)在特定疗法方面取得了显著进展。雷特综合征是一种独特的神经发育障碍,于 1966 年首次被描述,在哈格伯格及其同事于 1983 年发表具有里程碑意义的论文之前,该病一直进展缓慢。此后,该病取得了突飞猛进的发展,包括制定了具体的诊断标准,并积极寻找遗传病因,结果在 16 年后发现了位于 Xq28 的甲基-CpG 结合蛋白(MECP2)基因的变异。此后不久,美国国立卫生研究院罕见病办公室于 2003 年资助了 RTT 自然史研究(NHS),开始从大量 RTT 患者中获取有关临床特征的自然史数据。这些信息对于推进临床试验,为该疾病提供特异性疗法至关重要。在此过程中,成立了国际雷特综合征协会(IRSA)(现为国际雷特综合征基金会-IRSF),该协会直接参与了鼓励和扩大 NHS 注册人数的工作,随后又参与了 SCOUT 计划的开发,以促进在 RTT 小鼠模型中测试潜在的治疗药物。会议的总体目标是回顾从 NHS 研究中得出的临床特征,并讨论针对这种进行性神经发育障碍的特定疗法的现状。NHS 研究提供了有关 RTT 的关键信息:生长、人体测量学、寿命、主要合并症(包括癫痫、呼吸异常、胃食管功能障碍、脊柱侧凸和其他矫形问题)、青春期、行为和焦虑以及进行性运动退化(包括出现帕金森病特征)。研究还注意到表型与基因型的相关性,包括 X 染色体失活的作用。临床严重程度和生活质量测量方法的开发对于后续的临床试验也至关重要。此外,生化和神经生理学生物标志物的开发为临床试验提供了更多终点。国家医疗服务体系之前的最初临床试验效果不佳,但国家医疗服务体系和全球其他研究取得的进展引起了制药公司的极大兴趣,并促成了多项临床试验。虽然其中一些临床试验没有取得成果,如沙立唑坦,但其他一些临床试验却很有希望,包括美国食品和药物管理局(FDA)于 2023 年批准了特罗菲奈肽(trofinetide),这是第一种可用于专门治疗 RTT 的药物。Blarcamesine 已在 3 期试验中试用,14 种药物已在 2 期试验中研究,7 种药物正在临床前/横向研究中评估。盖伊等人在 2007 年进行的一项具有里程碑意义的研究表明,在无效小鼠模型中激活正常的 MECP2 基因可显著改善病情。基因替代疗法已通过转化研究推进到目前的两项 1 / 2 期临床试验(Taysha102 和 Neurogene-401)。其他基因疗法也在研究之中,包括基因编辑、RNA 编辑和 X 染色体再激活。总之,在过去的 40 年中,人们在了解和治疗 RTT 方面取得了显著进展。这表明,进一步的进步是可以期待的。
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引用次数: 0
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