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BOSTON--(BUSINESS WIRE)--Newleos Therapeutics, Inc., a clinical-stage biotechnology company developing innovative treatments for neuropsychiatric disorders, today announced the appointment of Stephen (Steve) Brannan, M.D., to its Board of Directors. Dr. Brannan is an expert in neuroscience and neuropsychiatric drug development with a proven track record of developing innovative medicines through regulatory approval and commercialization. Most recently, he served as Chief Medical Officer at Karuna Therapeutics (acquired by Bristol Myers Squibb in 2024 for $14 billion) where he led the clinical strategy for KarXT (xanomeline–trospium), the first new mechanism of action for schizophrenia approved in over 30 years. With the initiation of our Phase 1b studies in the EU, we are building upon the established safety and tolerability profile of NTX-1955 as we take an important step toward validating this novel mechanism in humans and advancing a new class of anxiolytics. Newleos also announced the filing of clinical trial applications (CTAs) with the competent health authorities for two Phase 1b studies of NTX-1955 to be conducted in the European Union (EU). Dosing has already commenced for one of the studies. Both studies will utilize a well-established, controlled, and reproducible clinical model to assess the anxiolytic effects of NTX-1955, as well as other tests designed to measure a wide range of central nervous system (CNS) effects in a pharmacological context. “We are thrilled to welcome Steve to the Newleos Board of Directors,” said David Donabedian, Ph.D., Founding Chief Executive Officer of Newleos Therapeutics and Executive Partner at Longwood Fund. “Steve brings an extraordinary track record in neuroscience drug development, having led the clinical strategy behind one of the most significant CNS breakthroughs of the past decade. His expertise in designing rigorous, patient-centered trials and navigating a variety of development paths will be invaluable as we initiate clinical studies for NTX-1955 in anxiety and begin to generate data across our pipeline more broadly. We look forward to his insights as we work to deliver meaningful innovation for people living with anxiety and other neuropsychiatric conditions.” “I’m excited to join the Newleos Board at such a pivotal time,” said Dr. Brannan. “The team’s patient focus and commitment to scientific rigor is clear, and I believe their innovative approach to targeting neuropsychiatric disorders has strong potential to address major unmet needs in the field.” In addition to Karuna, Dr. Brannan has held senior roles in clinical development and medical affairs, including Therapeutic Head of Neuroscience at Takeda, Vice President for Clinical Research and Medical Affairs at Forum Pharmaceuticals, and senior roles at Novartis, Cyberonics, and Eli Lilly. He has been active in the development of multiple important CNS treatments including Cymbalta, Exelon Patch, Trintellix, and VNS for treatment-resistant depression. Prior to joining the pharmaceutical industry, Dr. Brannan was a faculty member at the University of Texas Health Science Center at San Antonio (UTHSCSA), specializing in mood and anxiety patient care, running a clinical research unit, and conducting neuroimaging research. He trained in psychiatry at UTHSCSA and holds an M.D. from the University of Texas Health Science Center at Dallas. He has over 60 publications and routinely speaks at industry conferences. “There remains a profound unmet need for safe, effective, and fast-acting treatments for generalized anxiety disorder, which continues to impact tens of millions of people worldwide,” said Federico Bolognani, M.D., Ph.D., Co-founder and Chief Medical Officer of Newleos Therapeutics. “While current therapies often fall short due to limited efficacy or unacceptable side effects, NTX-1955 represents a fundamentally different approach. By selectively modulating GABAA-γ1 receptors, we aim to preserve the potent anxiolytic effects of GABAergic modulation while minimizing the sedation, cognitive impairment, and dependence risks seen with benzodiazepines. With the initiation of our Phase 1b studies in the EU, we are building upon the established safety and tolerability profile of NTX-1955 as we take an important step toward validating this novel mechanism in humans and advancing a new class of anxiolytics.” About Generalized Anxiety Disorder Generalized anxiety disorder (GAD) is the second most common mental health disorder among adults (approximately 20 million adults in U.S. alone). GAD is characterized by restlessness, irritability, feeling on edge, being easily startled, and panic attacks. GAD can also be characterized by physical ailments such as muscle tension, fatigue, irritability, gastrointestinal symptoms, and headaches. Most GAD patients are poorly managed by approved pharmacological therapies such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and benzodiazepines. Specifically, while first-line SSRIs and SNRIs are ineffective in most patients, second-line benzodiazepines, while highly efficacious, are not recommended for long-term use due to sedation, potential for misuse and dependence, and cognitive impairment. About NTX-1955 NTX-1955 is a first-in-class GABAA-γ1 positive allosteric modulator (PAM), originally discovered by Roche and now in development for generalized anxiety disorder (GAD). GABAA is the major inhibitory neurotransmitter in the brain and positive allosteric modulation of the GABAA receptor is a well-validated approach for managing GAD symptoms. Nonselective GABAA PAMs such as benzodiazepines, while robust anxiolytics, modulate GABAA receptors throughout the entire brain, including in brain regions that lead to cognitive and sedative side effects. In contrast, NTX-1955 is designed to selectively engage GABAergic transmission in the amygdala, which is at the center of the brain’s regulation of anxiety and highly enriched for the GABAA-γ1 receptor subunit, thereby sparing brain networks associated with the safety liabilities of benzodiazepines. NTX-1955 has shown dose-dependent anxiolytic activity in several gold-standard preclinical anxiety models matching benzodiazepines' efficacy without the side effect profile seen with classical benzodiazepines. Further, NTX-1955 has completed multiple Phase 1 studies, including Single Ascending Dose, Multiple Ascending Dose, drug-drug interaction, and receptor occupancy studies, demonstrating that it is safe, well tolerated, brain penetrant and selective to GABAA-γ1. About Newleos Therapeutics, Inc. Newleos Therapeutics is dedicated to providing a new dawn or "eos" for the one in every eight people around the world who are suffering from mental illness. The company’s pipeline was licensed from Roche and focuses on innovative neuropsychiatric mechanisms of action that aim to reduce side effects and improve outcomes compared to the current standard of care. Newleos’ clinical-stage, oral small molecules target GABAA-γ1, V1a, TAAR1 and GABAA-α5, with first- or best-in-class potential in the treatment of general anxiety, social anxiety, substance use disorders, and cognitive impairment. Newleos was co-founded by Longwood Fund, Federico Bolognani, M.D., Ph.D., and William Martin, Ph.D., seasoned experts in company creation and CNS drug development. For more information visit www.newleos.com.

“点击蓝字 关注我们赵雪毕业于上海交通大学医学院。上海市精神卫生中心主治医师、上海市精神心理疾病临床医学研究中心秘书。主要研究方向为精神药物遗传药理学。主持上海市精神卫生中心院级课题、上海交通大学“医工交叉”等科研项目多项。作为主要研究人员参与国家自然科学基金、上海市申康医院发展中心“促进市级医院临床技能与临床创新三年行动计划”等多项纵向科研课题。作为研究骨干参与多项国际多中心和国内多中心（牵头）临床试验。以第一（含共一）作者发表多篇中英文学术论文。 抗精神病药、抗抑郁药与不宁腿综合征 PPS 郭瑛睿1，钱瑞仪1，禹顺英2，沈一峰3，赵雪3*（1.上海交通大学医学院附属精神卫生中心精神科，上海 200030；2.上海交通大学医学院附属精神卫生中心遗传室，上海 200030；3.上海交通大学医学院附属精神卫生中心临床研究中心，上海 200030）[摘要] 不宁腿综合征（restless legs syndrome,RLS）是抗精神病药和抗抑郁药的常见不良反应之一，影响患者夜间睡眠、加重精神症状、降低患者生活质量，但其在临床实践尚未受到广泛重视。针对抗精神病药和抗抑郁药的 RLS 发生风险，这两类药物导致 RLS 的可能机制及相关治疗手段进行综述，以期为 RLS 的临床治疗提供参考。 不宁腿综合征（restless legs syndrome，RLS）又称不安腿综合征，是临床常见的运动感觉性神经系统疾病，主要表现为强烈、迫切想要移动肢体的冲动或欲望，常常伴随着肢体深处不舒服或难以描述的感觉，夜间睡眠或安静时出现或加重，具有昼夜节律性，按摩或活动后缓解，可导致严重睡眠障碍。在《精神障碍诊断与统计手册（第 5 版）》（the fifith edition of the diagnostic and statistical manual of mental disorders，DSM-5）中， RLS属于睡眠-觉醒障碍中异常睡眠的一类疾病。一般人群中RLS的发病率为 3%~19%，女性发病率更高[1]，其中约有2.5%的患者症状严重到需要接受医疗干预[2]。根据病因不同，RLS可分为原发性和继发性2种类型。原发性RLS通常在40岁之前发病，主要与遗传因素有关。继发性RLS伴发于各类躯体疾病，如神经系统疾病、铁缺乏症、慢性肾功能衰竭、糖尿病、自身免疫性疾病、甲状腺疾病、血管疾病、精神疾病等[1, 3-4]。RLS也是精神类药物的不良反应之一。据报道，抗精神病药、抗抑郁药和抗癫痫药是引起RLS最常见的3类药物[1]。早在1999年，1例病案报告指出奥氮平可能导致RLS[5]，此后越来越多的精神类药物被报道能够诱发RLS这一不良反应，不同药物发生RLS的风险有所不同。如上所述，引起RLS的精神类药物主要为抗精神病药及抗抑郁药，故本文主要针对抗精神病药和抗抑郁药引起RLS的发生风险，这两类药物导致RLS的可能机制及相关治疗手段进行综述。1抗精神病药、抗抑郁药与不宁腿综合征 Elrassas等[6]开展的横断面研究结果显示，200名接受抗抑郁药和抗精神病药治疗的患者中，服用第1代抗精神病药（除氟哌啶醇外）的患者发生RLS比 例最高（58.7%），其次是选择性5-羟色胺再摄取抑制剂（selective serotonin reuptake inhibitors，SSRIs）类药物（52.6%）和阿立哌唑（46.4%），接受曲唑酮（24.2%）和氟哌啶醇（31%）治疗的患者发生RLS可能性最小。 1.1 抗精神病药与不宁腿综合征有研究结果显示，与对照组（9.3%）相比，接受抗精神病药治疗的精神分裂症患者发生RLS的概率（21.4%）明显更高[7]。在各类抗精神病药中，奥氮平、喹硫平和氯氮平引起RLS的报道最多[1]，利培酮、鲁拉西酮等药物引起RLS的报道相对较少（见表1[5,8-29]）。也有部分研究结果显示，喹硫平和阿立哌唑能够改善其他抗精神病药引起的RLS症状[11,30]，可能是因为相对于多巴胺D2受体，这2种药物对5-羟色胺（5-hydroxytryptamine，5-HT）受体具有更高亲和力。另有研究报道，抗精神病药与抗抑郁药联用，如喹硫平与文拉法辛[31] 或帕罗西汀[18] 联用会导致RLS，停用2种药物中的一种会改善RLS症状。1.2 抗抑郁药与不宁腿综合征在多种抗抑郁药中，SSRIs、5-HT和去甲肾上腺素再摄取抑制剂（ serotonin-norepinephrine reuptake inhibitors，SNRIs）、四环类非典型抗抑郁药米氮平导致RLS的报道较多（见表2[32-46]）。Cetin Erdem 等[47]报道，在198名接受4~8周SSRIs/SNRIs药物治疗的门诊患者中，RLS的发生率为25%。与女性相比，男性使用抗抑郁药后发生RLS的风险增加[48]。Kolla等[49]报道，在各种抗抑郁药中，米氮平可能与较高的RLS发生率有关，也会恶化患者原有的RLS症状[50]，其次是文拉法辛，而安非他酮可能会减轻RLS症状。当联合使用2种或2种以上药物时，如氟西汀与米氮平联用[51]、帕罗西汀与度洛西汀联用[52]、艾司西酞普兰与锂盐或喹硫平联用[53]，患者发生RLS的风险也会相应增加。关于新型抗抑郁药伏硫西汀是否增加RLS风险的研究结果并不一致，有研究发现其可减轻RLS症状[54-55]，但也有研究报道伏硫西汀可诱发RLS[45]。2抗精神病药、抗抑郁药引起不宁腿综合征的可能机制2.1 多巴胺功能紊乱既往神经影像学研究表明，RLS患者脑内存在多巴胺能活性低下表现[56]。RLS包括运动和感觉异常两个维度的症状表现，感觉和运动回路受脊髓投射至大脑的相关区域控制，这些区域与不同神经递质有关，包括背区（5-HT）、丘脑区（去甲肾上腺素）和下丘脑后方的A11区（多巴胺）[57]。多巴胺受体激动剂是治疗RLS的一线药物，多巴胺拮抗剂（如抗精神病药）则会诱发RLS，提示多巴胺活性在RLS中的重要作用。抗精神病药与抗抑郁药增加RLS风险的具体机制目前尚不明确，多巴胺能活性降低被认为可能是抗精神病药诱发RLS的主要原因。阿立哌唑为多巴胺（D2、D3、D4）受体部分激动剂，正电子发射断层显像（positron emission tomography，PET）研究表明在治疗剂量下阿立哌唑受体占有率为95%[58]，阿立哌唑通过激动多巴胺受体改善RLS症状，该效果与罗匹尼罗和普拉克索等多巴胺受体激动剂相似。然而，与其他非典型抗精神病药物（如利培酮）相比，氯氮平和喹硫平的D2受体占有率较低，如果多巴胺功能降低能够诱发RLS，这些药物诱发RLS的可能性应该较小，这与多数研究报道不符。另有研究者认为，喹硫平因其镇静催眠作用，常在夜间使用可改善患者睡眠，而夜间多巴胺受体敏感性较白天增加[59]；另外，喹硫平常被用来与抗抑郁药（如SSRIs、米氮平等）合用改善情感症状，而抗抑郁药能够通过增加5-HT功能减少多巴胺释放 [60]，增加RLS发生风险。此外，有研究表明泌乳素（prolactin，PRL）水平可能在抗精神病药所致 RLS中起重要作用。多巴胺受体激动剂如左旋多巴和卡麦角林能够降低泌乳素水平，这2种药物均可以治疗RLS[61]。抗精神病药（如利培酮、奥氮平）能够增加PRL水平[62]，可能是引起RLS症状的间接原因。阿立哌唑可以降低抗精神病药引起的高泌乳素血症[63]，可能是阿立哌唑能够缓解RLS症状的另一原因 [23]。2.2 铁缺乏有研究发现，RLS患者脑脊液中铁蛋白含量减少[64] 及转铁蛋白含量升高；脑影像学研究也发现，RLS患者大脑中铁含量减少[65]；RLS患者尸检脑神经胶质细胞中铁含量较低[66]。外周铁水平正常的RLS患者补充铁剂也能改善RLS症状，可能是因为血脑屏障使大脑中铁水平独立于外周铁水平[67]。此外，脑内铁水平降低也会导致多巴胺代谢和D2受体状态改变，尤其是在黑质和壳核区域[9]。目前有研究发现，抗精神病药能够影响体内铁稳态[68]和肝脏铁代谢[69]，引起低铁血症。目前仍缺乏直接证据表明使用抗精神病或抗抑郁药出现RLS的患者是否存在外周或中枢铁代谢异常，仍需更多研究证据来明确这一可能机制。 2.3 遗传因素遗传因素是RLS的重要致病因素，大部分家族性RLS呈常染色体显性遗传，少数家族则呈常染色体隐性遗传或非孟德尔遗传模式[70]。既往遗传学研究多集中于原发性 RLS，全基因组关联研究发现位于不同染色体的 RLS 风险基因，包括BTBD9基因（位于染色体6p21）、MEIS1基因（位于染色体2p14）、PTPRD 基因（位于染色体9p24.1-p23）、MAP2K5/SKOR1 基因（位于染色体15q23）和TOX3/BC034767 基因（位于染色体 16q12.1）[71]。近期有研究发现7个全新的RLS易感基因位点：RLS1（位于染色体12q12-q21）、RLS2（位于染色体 14q13-q21）、RLS3（位于染色体 9p24-p22）、RLS4（ 位 于 染 色 体 2q33）、RLS5（ 位 于 染 色 体20p13）、RLS6（位于染色体 19p13）及RLS7（位于染色体16p12.1）[72-73]。截至目前，抗精神病药或抗抑郁药所致RLS的遗传学研究仍较少。有研究发现，MAOA基因VNTR与MAOB基因A644g多态的单倍型频率与抗精神病药引起RLS严重程度有关[74]。另一项研究显示，MAP2K5基因多态性增加了抗精神病药物诱发RLS的风险[75]。3抗精神病药、抗抑郁药引起不宁腿综合征的治疗RLS的治疗分为非药物治疗和药物治疗。非药物治疗包括：消除或减少继发性因素的影响，如尽量避免使用能够诱发或加重RLS的药物（如多巴胺受体拮抗剂、抗抑郁药、抗组胺药等）；保持良好的睡眠卫生习惯；加强体育锻炼；结合物理治疗（如重复经颅磁刺激、重复经颅电刺激）等。药物治疗包括：多巴胺激动剂（如罗匹尼罗、罗替戈汀、普拉克索），α2δ钙通道配体类药物（如普瑞巴林、加巴喷汀-恩那卡比、加巴喷汀），这些药物均为治疗RLS的一线用药 [76]，也可使用苯二氮䓬类镇静药[77] 和抗癫痫药[78] 等。治疗抗精神病药或抗抑郁药引起的RLS具有一定挑战性，目前仍缺乏高水平临床研究或相关指南指导医生用药。在既往相关病例报道中，临床医生一般采取减量或停用现用药物，加用多巴胺受体激动剂或α2δ钙通道配体类药物（具体病例处理方式可参考表1和表2），上述策略均能够有效改善患者RLS症状。值得注意的是，多巴胺受体激动剂和α2δ钙通道配体类药物可能会导致患者精神症状波动或病情复发。在既往病案报道中，加用小剂量阿立哌唑也是改善 RLS症状的常用手段，阿立哌唑剂量为1~10 mg·d-1[23,30]，在临床实践中医生可根据患者具体情况探索使用阿立哌唑的剂量。铁缺乏是RLS病理生理学中重要假说之一。在患者出现RLS症状后，医生可以通过相关检测指标（包括铁蛋白、转铁蛋白、血清铁、总铁结合力、转铁蛋白饱和度等）评估患者外周铁储存情况。如果患者确实存在缺铁表现，可采用铁替代疗法，如口服硫酸亚铁，若患者不能耐受或有效吸收口服铁剂，也可考虑静脉补铁，同时补充维生素C有助于促进消化道对铁的吸收[76]。在补充铁剂后，需动态观察患者RLS症状改善和评估外周铁相关指标变化。4结语 精神障碍患者常合并睡眠障碍，而RLS会进一步加重患者睡眠问题，同时伴有强烈心理不适感。此外，RLS能够增加肥胖、抑郁症、焦虑症、高血压及其他心血管疾病的发生风险，显著降低患者生活质量、延缓患者康复[79]。Cetin Erdem等[47]的研究显示，服用抗抑郁药发生RLS的患者生活质量显著下降。一项回顾性队列研究发现，自杀和自残风险与RLS呈正相关[80]。尽管在临床实践中，使用抗精神病药或抗抑郁药后出现RLS的病例并不少见，但与其他药物不良反应（如心血管不良反应、代谢综合征等）相比，RLS仍未得到有效识别和广泛重视。尤其在患者用药后出现新发睡眠问题时，不能简单地归结为疾病症状的一部分，应仔细识别是否存在RLS的可能性。目前关于精神类药物引起RLS的各方面研究仍较少，后续需要更多关注和探索，从而更好地为患者及临床服务。参考文献：[1]Patatanian E, Claborn M K. 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Association of restless legs syndrome with risk of suicide and self-harm[J]. JAMA Netw Open, 2019, 2(8): e199966.美编排版：覃冰冰感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2025年第 6 期。《药学进展》杂志由教育部主管、中国药科大学主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。联系《药学进展》↓↓↓编辑部官网：pps.cpu.edu.cn；邮箱：yxjz@163.com；电话：025-83271227。欢迎投稿、订阅！往期推荐聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航我知道你在看哟