Duloxetine Hydrochloride

*仅供医学专业人士阅读参考在精神分裂症患者中，治疗抵抗通常指对两种一线抗精神病药物在足量足疗程使用后仍无显著疗效。约25%的初发精神分裂症患者会发展为治疗抵抗精神分裂症（又称为难治性精神分裂症，TRS），而在多次复发的患者中，这一比例可能高达40%。氯氮平是当前治疗TRS最有效的药物，但是也只有40%-50%的TRS患者对氯氮平治疗产生充分反应。一些随机对照试验表明，在氯氮平基础上联合抗抑郁药可能有助于TRS患者症状改善，但是整体证据质量有限，且缺乏长期随访数据。来自东芬兰大学的研究人员基于芬兰和瑞典的全国性队列研究，讨论了联合抗抑郁药物对氯氮平治疗TRS的有效性和安全性。研究结果发表在《柳叶刀·精神病学》杂志上。研究共纳入了23206名氯氮平使用者，结果显示，氯氮平联合标准剂量的舍曲林（30-45mg/天），与TRS复发风险降低51%有关，艾司西酞普兰、度洛西汀等联合使用也与TRS复发风险显著降低有关，且在低剂量或标准剂量使用时未观察到躯体原因住院风险增加。研究数据来自芬兰和瑞典的全国性患者登记系统或住院出院登记系统，随访起始时间为精神分裂症确诊日期或首次使用氯氮平日期（取较晚值），随访结束时间为死亡、移民或数据截止时间。采用个体内分析，每位受试者为自身对照，最大程度减少偏倚，主要暴露因素为特定抗抑郁药物联合氯氮平的使用情况。药物使用数据来自处方药登记系统，抗抑郁药物联合治疗期间，患者同时使用氯氮平和一种抗抑郁药（本研究覆盖的抗抑郁药包括西酞普兰、艾司西酞普兰、氟西汀、帕罗西汀、舍曲林、度洛西汀等）。研究主要结局为精神分裂症复发（指因精神病性症状住院），次要结局为躯体原因住院（非精神障碍相关的躯体原因住院）。研究队列共包括23206名受试者，41%为女性，平均年龄为41.3岁，芬兰组和瑞典组中分别有约50%的受试者使用了抗抑郁药。最常用的抗抑郁药为西酞普兰、舍曲林和艾司西酞普兰。芬兰组和瑞典组的中位随访时间分别为12.1年和11.4年，分别有9243名（65.8%）和4671名（51.0%）受试者发生复发，两种主要抗抑郁药物类型，选择性血清素再摄取抑制剂（SSRI）和去甲肾上腺素-血清素再摄取抑制剂（SNRI）均与精神分裂症复发风险下降有关，其中，舍曲林和度洛西汀与氯氮平联用，复发风险下降最显著。调整混杂因素后，舍曲林、度洛西汀和艾司西酞普兰仍然与精神分裂症复发风险下降显著相关。按照剂量对抗抑郁药物进行分析，30-54mg/天的舍曲林、6-10mg/天的艾司西酞普兰和18-32mg/天的度洛西汀的复发风险最低，这些药物低剂量使用时（<0.6 DDDs/天），也可以观察到与复发风险下降有关。安全性方面，氯氮平与安非他酮联用与较低的躯体原因住院风险有关，但是与艾司西酞普兰联用与住院风险较高有关。将抗抑郁药物按照剂量等级分类时，所有药物在低剂量或标准剂量下，均与躯体原因住院风险无关；但是中高剂量（1.1-2.1 DDDs/天）或高剂量（≥2.1 DDDs/天）与躯体原因住院风险增加有关。总的来说，研究表明，氯氮平与标准剂量的SSRI或SNRI联合使用，与精神分裂症复发风险降低有关，并且未发现严重躯体不良反应风险增加。但是，联合使用过程中，尚不清楚SSRI和SNRI会增加哪些具体的不良反应。高剂量抗抑郁药的使用可能本身代表抑郁症状加重或躯体状况恶化，因此也可能部分解释住院风险增加的结果。从安全性和疗效角度来看，应当谨慎使用高剂量抗抑郁药物。参考文献：Taipale H, Siskind D, Tanskanen A, Mittendorfer-Rutz E, Correll CU, Tiihonen J. Real-world effectiveness of clozapine augmentation with antidepressants: within-subject data evidence from two European nationwide cohorts. Lancet Psychiatry. 2025;12(8):568-578. doi:10.1016/S2215-0366(25)00163-4本文作者丨王雪宁

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.