A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Patients With Major Depressive Disorder With an Inadequate Response to Current Antidepressant Treatment

The purpose of this study is to evaluate the safety, tolerability, and efficacy of TS-121 as an adjunctive treatment for patients with major depressive disorder with an inadequate response to current antidepressant Treatment (SSRI, SNRI or bupropion).

开始日期2017-07-03

申办/合作机构

Taisho Pharmaceutical R&D, Inc.

NCT02448212

/ Completed临床1期

A Phase 1 Receptor Occupancy Study Using Positron Emission Tomography to Investigate Novel Ligand [11C]TASP0410699 Alone and Following Single Oral Dose Administrations of TS-121 in Healthy Adult (Male) Subjects

The purpose of this study is to evaluate the binding of a novel tracer, [11C]TASP0410699, using Positron Emission Tomography (PET) scans with or without dosing of TS-121

开始日期2015-05-01

申办/合作机构

Taisho Pharmaceutical R&D, Inc.

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项与 Brezivaptan 相关的文献（医药）

2022-04-01·JOURNAL OF NUCLEAR MEDICINE1区 · 医学

Imaging Pituitary Vasopressin 1B Receptor in Humans with the PET Radiotracer ¹¹C-TASP699

1区 · 医学

Article

作者: Zhang, Ming-Rong ; Naganawa, Mika ; Huang, Yiyun ; Gao, Hong ; Sabia, Helene ; Henry, Shannan ; Pracitto, Richard ; Carson, Richard E ; Ozaki, Satoshi ; Matuskey, David ; Nishino, Izumi ; Ropchan, Jim ; Suhara, Tetsuya ; Nabulsi, Nabeel B ; Lin, Shu-Fei ; Labaree, David

Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V_1A, V_1B, and V₂). Among these subtypes, the V_1B receptor (V_1BR), highly expressed in the pituitary, is a primary regulator of hypothalamic-pituitary-adrenal axis activity and thus a potential target for treatment of neuropsychiatric disorders such as depression and anxiety. N-tert-butyl-2-[2-(6-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (TASP699) is a novel PET radiotracer with high affinity and selectivity for V_1BR. The purpose of this study was to characterize the pharmacokinetic and binding profiles of ¹¹C-TASP699 in humans and determine its utility in an occupancy study of a novel V_1BR antagonist, TS-121. Methods: Six healthy subjects were scanned twice with ¹¹C-TASP699 to determine the most appropriate kinetic model for analysis of imaging data and test-retest reproducibility of outcome measures. Nine healthy subjects were scanned before and after administration of TS-121 (active component: THY1773) to assess V_1BR occupancy. Metabolite-corrected arterial input functions were obtained. Pituitary time-activity curves were analyzed with 1- and 2-tissue-compartment (1TC and 2TC, respectively) models and multilinear analysis 1 (MA1) to calculate distribution volume (V _T). Relative test-retest variability (TRV) and absolute TRV were calculated. Since no brain region could be used as a reference region, percentage change in V _T after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentrations of the drug. Results: ¹¹C-TASP699 showed high uptake in the pituitary and no uptake in any brain region. The 2TC model provided better fits than the 1TC model. Because the MA1 V _T estimates were similar to the 2TC V _T estimates, MA1 was the model of choice. The TRV of V _T was good (TRV, -2% ± 14%; absolute TRV, 11%). THY1773 reduced V _T in a dose-dependent fashion, with a half-maximal inhibitory concentration of 177 ± 52 ng/mL in plasma concentration. There were no adverse events resulting in discontinuation from the study. Conclusion: ¹¹C-TASP699 was shown to display appropriate kinetics in humans, with substantial specific binding and good reproducibility of V _T Therefore, this tracer is suitable for measurement of V_1BR in the human pituitary and the V_1BR occupancy of TS-121, a novel V_1BR antagonist.

2021-05-01·Biopharmaceutics & drug disposition4区 · 医学

Prediction of a clinically effective dose of THY1773, a novel V_1Breceptor antagonist, based on preclinical data

4区 · 医学

Article

作者: Hiromi Endo ; Makoto Kamiya ; Izumi Nishino ; Helene D. Sabia ; Akiko Mizuno-Yasuhira ; Shoko Inatani

Abstract:

THY1773 is a novel arginine vasopressin 1B (V1B) receptor antagonist that is under development as an oral drug for the treatment of major depressive disorder (MDD). Here we report our strategy to predict a clinically effective dose of THY1773 for MDD in the preclinical stage, and discuss the important insights gained by retrospective analysis of prediction accuracy. To predict human pharmacokinetic (PK) parameters, several extrapolation methods from animal or in vitro data to humans were investigated. The fu correction intercept method and two‐species‐based allometry were used to extrapolate clearance from rats and dogs to humans. The physiologically based pharmacokinetics (PBPK)/receptor occupancy (RO) model was developed by linking free plasma concentration with pituitary V1B RO by the Emax model. As a result, the predicted clinically effective dose of THY1773 associated with 50% V1B RO was low enough (10 mg/day, or at maximum 110 mg/day) to warrant entering phase 1 clinical trials. In the phase 1 single ascending dose study, TS‐121 capsule (active ingredient: THY1773) showed favorable PKs for THY1773 as expected, and in the separately conducted phase 1 RO study using positron emission tomography, the observed pituitary V1B RO was comparable to our prediction. Retrospective analysis of the prediction accuracy suggested that the prediction methods considering plasma protein binding, and avoiding having to apply unknown scaling factors obtained in animals to humans, would lead to better prediction. Selecting mechanism‐based methods with reasonable assumptions would be critical for the successful prediction of a clinically effective dose in the preclinical stage of drug development.

2020-09-01·Journal of psychiatric research2区 · 医学

Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study

2区 · 医学

Article

作者: Fava, Maurizio ; Marella, Julie ; Chaki, Shigeyuki ; Iijima, Michihiko ; Kamiya, Makoto ; Nishino, Izumi ; Umeuchi, Hideo ; Sabia, Helene D ; Nemeroff, Charles B

Vasopressin 1B (V_1B) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V_1B receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V_1B receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018. The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD.

项与 Brezivaptan 相关的新闻（医药）

2025-07-18

·药学进展

独家原创 | 沈一峰主任医师：从靶点机制到临床应用解析抗抑郁药的研发进展

“点击蓝字关注我们沈一峰医学博士，主任医师，硕士生导师。现任上海市精神卫生中心药物临床试验机构办主任。美国临床研究专业协会认证研究医生，中国药学会药物临床评价研究专委会副主任委员。Rutger New Jersey Medical School 高级访问学者（2015—2016 年）。从事精神心理疾病的临床评估和诊治研究 20 余年。以抑郁症和精神分裂症为代表，研发电子化量表和客观评价工具，探讨患者需求和偏好、不同治疗药物的暴露-效应关系、机制验证研究、药物基因组学特征、常见不良反应和相关因素。担任国家“重大新药创制”科技重大专项：精神药物新药临床评价研究技术平台副组长（2008—2020 年），主持科研项目 7 项，发表文章80余篇，H 指数12。从靶点机制到临床应用解析抗抑郁药的研发进展 PPS 王竹馨 1，魏宇梅 2，吴瑛 2，黄志伟 2，李华芳 2，赖水琴 1，张庆 1*，沈一峰 2**（1. 艾昆纬医药科技（上海）有限公司临床运营卓越中心，上海 200124；2. 上海交通大学医学院附属精神卫生中心，上海 200030）[摘要] 近年来，新型抗抑郁药物的开发取得了较大进展，其中一些药物已逐渐应用于临床。单胺氧化酶抑制剂（monoamine oxidase inhibitors, MAOIs）、三环类药物（tricyclic antidepressants, TCAs）、γ- 氨基丁酸(γ-aminobutyric acid, GABA）/ 谷氨酸能药物及其他新靶点药物的不断涌现，为抑郁症患者提供了更多治疗选择。综述近几年抗抑郁药的临床研发现状及全球管线情况，通过对不同靶点抗抑郁药的临床意义、市场现状、研发格局及在研管线的详细分析，旨在为相关研究人员和临床医生提供参考。抗抑郁药的研究与开发一直备受关注。从最初偶然发现的初代抗抑郁药如单胺氧化酶抑制剂（monoamine oxidase inhibitors，MAOIs）和三环类药物（tricyclic antidepressants，TCAs），到基于抑郁症致病机制和分子生物学研究设计的选择性 5-羟色胺再摄取抑制剂（selective serotonin reuptake inhibitors ， SSRIs）以及 5-羟色胺（5-hydroxytryptamine，5-HT ）和去甲肾上腺素抑制剂（serotonin and norepinephrine reuptake inhibitors ，SNRIs）等，再到作用于谷氨酸能和 γ-氨基丁酸( γ-aminobutyric acid ，GABA）靶点的速效抗抑郁药，抗抑郁药的作用靶点和机制探索日趋丰富。理解不同靶点生理作用及其临床意义，不仅可深化对抑郁症的病理机制的了解、优化临床用药的实践，更有助于开发在疗效和安全耐受性方面更具优势的创新抗抑郁药。本文综述了近几年抗抑郁药的临床研发现状及管线情况，通过对不同靶点抗抑郁药的临床意义、市场现状、研发格局及在研管线的详细分析，旨在为相关研究人员和临床医生提供参考。1 抗抑郁药的靶点与临床意义1.1 单胺氧化酶抑制剂与三环类抗抑郁药MAOIs 和 TCAs 是最早开发和使用的抗抑郁药物，其核心作用机制均通过非选择性调控单胺递质系统达到抗抑郁效果[1] 。然而，MAOIs 和 TCAs 的非选择性的多靶点特性导致疗效与风险并存。MAOIs 通过抑制脑内单胺神经递质的代谢提高突触递质浓度，发挥抗抑郁作用。该类药物“广谱增效”的特点使其在治疗顽固性抑郁症及伴焦虑与疼痛的复杂型抑郁症具有独特的优势。然而， MAOIs 的缺点也较明显，如服用 MAOIs 的患者需要避免摄入富含酪胺的食物（如陈年奶酪、红酒、腌制肉类等），因可能会引发严重的高血压反应，其次 MAOIs 与其他药物，包括一些常见的非处方药和处方药有潜在危险的相互作用，这要求患者在使用其他药物前必须咨询医生。此外， MAOIs 常见的不良反应还包括睡眠障碍、恶心和头晕等，非选择性的 MAOIs 还有导致直立性低血压的风险 [2]。上述因素限制了MAOIs 的临床使用，使其逐步退居为二线用药。TCAs 通过抑制去甲肾上腺素（norepinephrine， NE）和 5-HT 的再摄取过程，增强神经递质的可利用性。TCAs 的优势在于治疗慢性和重度抑郁症的效果更好，特别是对于复杂的抑郁症病例可能较有效。然而，TCAs 对 α1 肾上腺素受体、毒蕈碱性乙酰胆碱受体及钠离子通道的拮抗和调节作用，可能导致抗胆碱能反应（口干、便秘）和心脏毒性问题突出，严重时甚至危及生命 [3] ，提示临床医生在开具处方时需谨慎评估患者的健康状况和使用风险。与新型抗抑郁药物相比，TCAs 往往需要更长时间才会显现疗效，对于亟待缓解症状的患者而言可能不理想。1.2 单胺类抗抑郁药基于单胺假说的深入发展，抑郁症被认为是脑内 5-HT、NE 和多巴胺（dopamine，DA）水平失衡所导致的结果。SSRIs 和 SNRIs 是目前临床上最常用的单胺类抗抑郁药。SSRIs 通过选择性阻断突触前 5-HT 转运蛋白来发挥其治疗作用。相较于 MAOIs 和 TCAs ，SSRIs 的靶点精确定位实现了安全性突破，不良反应的发生频率和严重程度均大幅降低，对于孕妇和老年人等脆弱人群也较为安全。然而 SSRIs 也存在临床局限性：1)起效慢，可能需要数周才能显示出显著的抗抑郁效果。2)存在 5-HT 综合征风险，可能引起锥体外系症状，还会导致恶心、胃肠道反应和性功能障碍等不良反应。3)SSRIs 可能导致药物间相互作用，突然停用 SSRIs 可能诱发停药综合征，出现头痛、眩晕、情绪波动等症状，因此需要逐渐减量。SNRIs 通过协同调节 5-HT 和 NE 通路，其疗效谱系更广。对于 SSRIs 疗效欠佳的抑郁症患者，可从 SNRIs 治疗中获益。相较于 SSRIs ，SNRIs 及其代谢物对 CYP 酶的影响较低，不易产生严重的药物间相互作用。此外，SNRIs 和 TCAs 均可同时影响 5-HT 和 NE 通路，二者对抑郁症相关疼痛症状的疗效相似，但 SNRIs靶点选择度更高，不良反应更少。SNRIs 引起的不良反应与剂量有关，低剂量下 SNRIs 主要阻断 5-HT 再摄取，因此不良反应表现与 SSRIs 相似；中至高剂量下，SNRIs 对 5-HT 和 NE 再摄取均有阻断效果，因阻断 NE 再摄取而产生的不良反应包括出汗、心动过速、震颤、焦虑和高血压等。提示，未来抗抑郁药物研发需突破“单纯递质浓度调节”的局限，转向受体亚型特异性调控从而实现精准干预。除 SSRIs 和 SNRIs 外，还有一些作用于单胺神经递质通路但具体靶点不同的药物（见表1），其中部分药物对于特殊人群（如急性期患者、老年患者）具有更好的疗效，且不良反应相对更少。1.3 γ- 氨基丁酸/谷氨酸能抗抑郁药研究发现，抑郁症不仅与单胺神经递质有关，还涉及大脑、脑脊髓液和外周组织中其他神经递质的紊乱 [4] 。GABA 和谷氨酸是大脑中2 种重要的神经递质。GABA 是中枢神经系统的主要抑制性神经递质，GABA 合成减少或受体活性减退可导致神经元过度兴奋，影响情绪与认知。谷氨酸是主要的兴奋性神经递质，参与学习、记忆和神经可塑性。GABA/ 谷氨酸能抗抑郁药物直接作用于大脑中的关键神经递质系统，能够迅速调节神经元的活动，增强突触可塑性，促进新的神经连接的形成，从而快速改善情绪 [5] 。这些药物可通过静脉注射、鼻腔喷雾等多种途径给药，增加其使用的灵活性，如艾司氯胺酮通过鼻喷雾剂途径给药，在起效速度方面的临床优势显著，对于急需快速缓解症状的患者，尤其是有自杀风险的患者，具有重要的临床意义 [6-7]。然而，需警惕氯胺酮的分离性幻觉要求严格用药监护，长期神经可塑性改变的安全性仍需验证。提示，新一代抗抑郁药的研发需在“快速起效”与“长期安全”间寻求平衡。此外，对于一些特殊患者群体，如对传统抗抑郁药物反应不佳的难治性抑郁症患者及患有产后抑郁的妇女，GABA/谷氨酸能抗抑郁药提供了一种新的治疗选择。2019 年美国食品药品监督管理局（Food and Drug Administration，FDA）批准了一款突破性产品别孕烯醇酮用于治疗产后抑郁症。别孕烯醇酮通过静脉输注给药，通过正向调节 GABAA 受体，降低焦虑水平并减轻抑郁症状。一项针对哺乳期健康受试者的 Ⅰb 期临床研究表明，别孕烯醇酮给药后，四氢孕酮在血浆和母乳中的水平可被快速清除，对婴儿影响较小，实现了母婴安全性平衡 [8]。2抗抑郁药物市场现状根据最新的市场报告，全球抗抑郁药物市场在 2024 年的规模约为171.1 亿美元，将以 4.2% 的复合年增长率在 2025 年增长至 178.2 亿美元；预计抗抑郁药市场规模将在未来几年稳步增长，到 2029 年市场规模预计将达到 202.5 亿美元 [9]。自 2019 年 2 个里程碑式的产品艾司氯胺酮和别孕烯醇酮在美国上市，全球抗抑郁创新药上市速度明显加快，机制靶点和上市地区也更加丰富。2022—2023 年全球共有5 个抗抑郁新药上市（见表2）。吉哌隆是首款治疗成人抑郁症的口服选择性 5-HT1A 受体激动剂，自 2002 年起曾被美国FDA 拒绝上市申请多次，如今终获批准。舒拉诺龙是首个获批治疗产后抑郁症的口服药物，可在3天内改善症状，比目前用于治疗产后抑郁症的抗抑郁药起效更快 [10] 。舒拉诺龙的获批，标志着目前产后抑郁症的治疗模式发生了重大变化。肠道益生菌 Mokbio® 可通过调节肠道菌群平衡来减少抑郁症状 [11] 。 Auvelity®（安非他酮 + 右美沙芬）是美国 FDA 批准的首个口服速效抗抑郁药，在该复方制剂的组合中，右美沙芬主要作为 N-甲基-D-天冬氨酸受体（N-methyl-D-aspartic acid receptor，NMDAR）拮抗剂，安非他酮可增加右美沙芬的生物利用度，同时抑制 NE 和 DA 再摄取 [12] 。中国也上市了 5-HT/NE/DA 三重再摄取抑制剂若欣林 ®（托鲁地文拉法辛）[13] 。若欣林 ® 作为首款国产 1 类创新抗抑郁药，为在创新药领域积极探索的本土企业增加了信心，标志着我国从“快速跟随”向“自主创新”的战略转型。基于全球抗抑郁市场的逐渐活跃，中国抗抑郁药市场也呈现诸多积极的态势。在创新药领域，跨国企业已开始注重在中国的布局，如艾司氯胺酮于 2019 年在美国获批，2023 年即在中国上市。此外，中国本土企业除积极探索创新产品外，也在快速抢占抑郁症仿制药的市场，多个未在中国上市的创新产品的仿制药已获批或进入临床试验。3抗抑郁新药的研发格局截至 2024 年 6 月，全球处于在研状态（近 3 年内存在临床试验记录）的抗抑郁症创新药共计 77 个，约 2/3 的管线处于Ⅱ期临床试验阶段（见表 3）。与过去单胺类主导的研发模式不同，当前抗抑郁症创新药管线呈现“单胺深化 + 多靶点突破”的双轨格局。56% 的管线仍聚焦单胺及 GABA/ 谷氨酸通路，其余管线则探索阿片受体（opioid receptor ，OR）和食欲素受体（orexin receptor ，OX ）等新靶点。基于近几年抑郁症分子病因学的发展，全球有 19 个管线作用于常见神经递质和受体之外的新靶点，甚至涉及神经可塑性、炎症调控等新兴机制。另外，氘代技术通过稳定代谢路径，可延长药物半衰期、减少副作用，成为老药优化的新方向。4在研抗抑郁新药管线分析4.1作用于 GABA/ 谷氨酸能神经递质的抗抑郁药传统抗抑郁药多聚焦单胺靶点，而目前作用于氨基酸神经递质系统（GABA 和谷氨酸）的抗抑郁药是研发管线的热门，共有 18 个在研产品，其中有 6 个在中国进行研发（见表4）。传统单胺类药物（如 SSRIs）需 2~4 周起效，而 GABA/ 谷氨酸能药物（如氯胺酮）通过调节谷氨酸能突触可塑性在临床应用中可以实现快速（数小时内）抗抑郁，然而，其致幻性和成瘾性风险催生了对其结构优化和剂型创新等策略。例如，具有口服活性的氯胺酮结构类似物 GM1020 通过结构修饰，避免了静脉注射氯胺酮和艾司氯胺酮相关的不良反应，已针对重度抑郁症进行了Ⅱ期临床研究。新型长效注射剂通过剂型创新，可实现单次肌肉注射给药用于产后抑郁，提高用药的依从性和便利性，低口服生物利用度避免了母婴暴露，兼顾疗效与安全性。另外，值得关注的是，在靶向 GABAA 的管线中 PRAX 114 已进展到Ⅱ/Ⅲ期临床阶段，但在近期 Aria 研究中，尽管 PRAX-114 显示耐受性良好，但其疗效未能满足患者的需求，在主要终点上未达到统计学意义 [14] ，提示单纯增强 GABA 能活性可能不足以应对抑郁症的多维度病理，需结合其他通路调节。4.2 作用于单胺神经递质的抗抑郁药目前，全球单胺神经递质靶点相关在研抗抑郁药共 25 个，其中 32% 在中国开展研发（见表 5 ）。根据多靶点协同调控策略研发的药物包括 5-HT/ NE/DA 三重再摄取抑制剂 DB-104（liafensine）、 EB-1020 、OPC-64005 、JS1-1-01 以及 5-HT/NE 双重再摄取抑制剂 NH-102 等，此类药物通过协同调节不同递质系统，在临床应用中可能覆盖更广泛的症状谱，如情感麻木、快感缺失、认知障碍等。除上述多靶点策略外，致幻剂衍生药物的研究开创了 “快速抗抑郁 + 神经重塑”的路径。例如 ELE-101 通过 5-HT2A 受体部分激动/拮抗的分子设计，在保留裸盖菇素快速抗抑郁活性的同时，显著降低致幻作用。类似地，SPL-026 也是通过修饰二甲氧基色胺的侧链保留了抗抑郁活性的同时，减少了幻觉发生。目前国内外研究者正积极探索分子修饰策略，在保留致幻剂快速抗抑郁效果的同时，降低其致幻副作用 [15-16]。目前处于Ⅲ期临床阶段的单胺神经递质靶点抗抑郁药共有 3 个。Ulotaront 是一款具有 5-HT1A 激动剂活性的痕量胺相关受体 1（trace amine-associated receptor 1 ，TAAR1 ）激动剂，目前正在美国进行针对重度抑郁症的辅助性治疗的Ⅱ/Ⅲ期临床研究，其独特的机制可能为患者提供更有效的治疗选择，预计其研究结果将于 2025 年公布。嘧替佐酮是国内在研该类药物中进展最快的产品之一，自 2021 年7月启动Ⅱ/Ⅲ期临床研究以来，已取得显著进展，其快速的研发速度和潜在的疗效，使其备受关注。4.3 作用于阿片受体和食欲素受体的抗抑郁药除单胺类及 GABA/谷氨酸能系统等经典通路外，OR 和 OX 等新型神经递质受体在抑郁症病理生理中的作用正受到日益关注。OR 可通过异二聚化（heterodimerization）与 5-HT 和 DA 受体在功能上产生相互作用 [17] ，负向调节神经递质的释放 [18] 。临床前和临床研究表明， OR 系统通过调节社交行为、食欲、快感体验、奖赏机制及焦虑反应等多维度影响抑郁发生 [19] 。目前全球作用于 OR 的抗抑郁药管线有 3 个（见表6），其中短效 kappa 型阿片受体（kappa opioid receptor， KOR）拮抗剂 aticaprant 研究进展最快，已在全球开展针对抑郁症、快感缺失、焦虑障碍等适应证Ⅰ~ Ⅲ 期临床试验，并于 2023 年初获得中国Ⅲ期临床试验的默示许可，显示出其在精神治疗领域的广泛应用潜力。OX 是重要的神经肽类递质，除调控与抑郁密切相关的睡眠-觉醒、摄食等生理过程外，还可通过双向调节多个脑区的活动直接影响抑郁状态 [20] 。早在 2012 年进行的双重 OX 拮抗剂 filorexant 随机、双盲、对照Ⅱ期临床试验，受试者招募困难，且治疗组和安慰剂组的抑郁量表评分未能达到统计学意义上的差异 [21] 。目前在研的 2 个 OX 拮抗剂（见表6）转向选择性拮抗治疗策略，其中，选择性人类食欲素-2（orexin-2 ，OX2 ）受体拮抗剂 seltorexant 在 Ⅲ期临床试验 MDD3001 中，作为抗抑郁药的辅助治疗显示出显著的有效性和安全性，尤其对伴有失眠症状的抑郁症患者疗效显著，有望成为“first-in- class”的选择性 OX2 受体拮抗剂 [22]。4.4 其他新靶点抗抑郁药抑郁症的分子病因学和病理生理学机制复杂，受到遗传和环境等因素相互作用的影响。近年来，不同分子水平的大量研究发现，除了单胺和谷氨酸能神经递质及其传导机制外，抑郁症还与一系列人体和环境因素密切相关，如压力水平、神经系统发育、神经营养因子、表观遗传、免疫系统和炎症、肠道菌群等 [23-24]。这些因素中的许多已成为抗抑郁新药研发的新靶点，为抗抑郁药物的临床研发提供了新方向 [25] 。表7列举了全球范围内针对这些新靶点的19个抗抑郁药的临床研发管线，其中，Xanamem®和TS-121通过降低压力水平来缓解抑郁症状；ALTO-100通过增强神经营养因子效能促进神经网络重构；BI-1358894借助神经元离子通道调节改善突触传递；ZZ-2103通过调节肠道迷走神经信号改善中枢神经功能；MET-2靶向肠道微生物生态系统重塑等。目前，这些针对新靶点的抗抑郁药物中 68% 处于Ⅱ期临床试验阶段，显示出良好的临床应用前景。4.5 氘代抗抑郁药氘代药物作为一种新兴的药物研发方向，凭借其独特的同位素效应，在抗抑郁药物的开发中展现出广泛的应用潜力。目前，全球范围内有6个临床在研的氘代抗抑郁药物，其中有 2 个由中国本土企业在中国进行临床研发（见表8）。氘代技术通过选择性替换药物分子中的氢原子为氘原子（D），显著提高了药物在体内的代谢稳定性，延长了药物半衰期和生物利用度，进而增强了药物的安全性、耐受性和疗效 [26-28] 。氘代技术在保留原药药理活性的基础上，通过改变代谢路径选择性降低毒性中间体生成，达成“代谢分流” 与“毒性隔离”的双重优化目标，实现“老药新用” 的迭代升级，不仅减少了相关的药物不良反应，还极大地提升了患者在治疗过程中的用药体验。5结语与展望综上所述，抗抑郁药物的研发在过去几年中取得了显著进展，单胺类药物、GABA/谷氨酸能药物及其他新靶点药物的不断涌现，为抑郁症患者提供了更多的治疗选择。全球抗抑郁药物市场在创新驱动下保持稳健增长，新型药物上市周期明显缩短、作用靶点呈现多维度突破、治疗机制实现多元化创新。这标志着抗抑郁药研发已突破传统“单胺假说” 的理论框架，正式迈入多靶点协同、多模态干预的新时代。相较于传统药物，新型抗抑郁药物在起效速度、适应证覆盖和机制创新等方面取得突破性进展。然而，现有药物体系仍面临临床疗效个体差异显著、远期安全性数据不足等关键挑战，提示需建立更精准的生物标志物评价体系。未来，随着分子病因学和病理生理学研究的深入，更多具有创新靶点的抗抑郁药物有望进入临床应用。特别是在中国，随着本土企业在创新药物研发方面的积极探索和跨国企业的布局，中国抗抑郁药物市场将迎来更多机遇和挑战，中国药企需加强源头创新（如氘代技术、人工智能辅助药物设计等）并进一步深化临床转化研究。期待未来能有更多高效、安全的抗抑郁药物成功问世，为全球抑郁症患者带来康复的希望。参考文献：[1] Pereira V S, Hiroaki-Sato V A. A brief history of antidepressantdrug development: from tricyclics to beyond ketamine[J]. ActaNeuropsychiatr, 2018, 30(6): 307-322.[2] Krishnan K R. Revisiting monoamine oxidase inhibitors[J]. J ClinPsychiatry, 2007, 68(Suppl 8): 35-41.[3] Gillman P K. Tricyclic antidepressant pharmacology and therapeuticdrug interactions updated[J]. Br J Pharmacol, 2007, 151(6): 737-748.[4] Pan J X, Xia J J, Deng F L, et al. Diagnosis of major depressivedisorder based on changes in multiple plasma neurotransmitters: atargeted metabolomics study[J]. Transl Psychiatry, 2018, 8(1): 130.[5] Iadarola N D, Niciu M J, Richards E M, et al. Ketamine and otherN-methyl-D-aspartate receptor antagonists in the treatment ofdepression: a perspective review[J]. Ther Adv Chronic Dis, 2015,6(3): 97-114.[6] Ionescu D F, Fu D J, Qiu X, et al. Esketamine nasal spray for rapidreduction of depressive symptoms in patients with major depressivedisorder who have active suicide ideation with intent: results ofa phase 3, double-blind, randomized study (ASPIRE II)[J]. Int JNeuropsychopharmacol, 2021, 24(1): 22-31.[7] Fu D J, Ionescu D F, Li X, et al. Esketamine nasal spray for rapidreduction of major depressive disorder symptoms in patients whohave active suicidal ideation with intent: double-blind, randomizedstudy (ASPIRE I)[J]. J Clin Psychiatry, 2020, 81(3): 19m13191.[8] Wald J, Henningsson A, Hanze E, et al. Allopregnanoloneconcentrations in breast milk and plasma from healthy volunteersreceiving brexanolone injection, with population pharmacokineticmodeling of potential relative infant dose[J]. Clin Pharmacokinet,2022, 61(9): 1307-1319.[9] Research and Markets. Antidepressants global market report 2025[EB/OL]. (2025-03-31)[2025-04-08]. https://www.researchandmarkets.com/reports/5734971/antidepressants-global-market-report[10] Scientific American. First pill for postpartum depressionapproved[EB/OL]. (2023-08-07)[2024-08-21]. https://www.scientificamerican.com/article/first-pill-for-postpartum-depressionapproved.[11] Ho Y T, Tsai Y C, Kuo T B J, et al. Effects of Lactobacillus plantarumPS128 on depressive symptoms and sleep quality in self-reportedinsomniacs: a randomized, double-blind, placebo-controlled pilottrial[J]. Nutrients, 2021, 13(8): 2820.[12] Keam S J. Dextromethorphan/bupropion: first approval[J]. CNS Drugs, 2022, 36(11): 1229-1238.[13] Vasiliu O. Efficacy, tolerability, and safety of toludesvenlafaxine for the treatment of major depressive disorder-a narrative review[J]. Pharmaceuticals (Basel), 2023, 16(3): 411.[14] Praxis Precision Medicines. Praxis precision medicines reports negative results from PRAX-114 phase 2/3 monotherapy aria study in patients with major depressive disorder[EB/OL]. (2022-06-06)[2024- 08-23]. https://investors.praxismedicines.com/news-releases/news- release-details/praxis-precision-medicines-reports-negative-results-prax-11[15] De Gregorio D, Aguilar-Valles A, Preller K H, et al. Hallucinogens in mental health: preclinical and clinical studies on LSD, psilocybin, MDMA, and ketamine[J]. J Neurosci, 2021, 41(5): 891-900[16] Goodwin G M, Aaronson S T, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression[J]. N Engl J Med, 2022, 387(18): 1637-1648.[17] Pérez dela Mora M, Borroto-Escuela D O, Crespo-Ramírez M, et al. Dysfunctional heteroreceptor complexes as novel targets for the treatment of major depressive and anxiety disorders[J]. Cells, 2022, 11(11): 1826.[18] Reeves K C, Shah N, Muñoz B, et al. Opioid receptor-mediated regulation of neurotransmission in the brain[J]. Front Mol Neurosci,2022, 15: 919773.[19]Puryear C B, Brooks J, Tan L, et al. Opioid receptor modulation of neural circuits in depression: what can be learned from preclinical data?[J]. Neurosci BiobehavRev, 2020, 108: 658-678.[20] Fagan H, Jones E, Baldwin D S. Orexin receptor antagonists in thetreatment of depression: a leading article summarising pre-clinical and clinical studies[J]. CNS Drugs, 2023, 37(1): 1-12.[21] Connor KM, Ceesay P, HutzelmannJ, et al. Phase II proof-of-concept trial of the orexin receptor antagonist filorexant (MK-6096) in patients with major depressive disorder[J]. Int J Neuropsychopharmacol, 2017, 20(8): 613-618.[22] Johnson & Johnson. Johnson & Johnson pivotal study of seltorexant shows statistically significant and clinically meaningful improvement in depressive symptoms and sleep disturbance outcomes[EB/OL]. (2024-05-29) [2025-03-03]. https://www.jnj.com/media-center/ press-releases/johnson-johnson-pivotal-study-of-seltorexant-shows- statistically-significant-and-clinically-meaningful-improvement-in- depressive-symptoms-and-sleep-disturbance-outcomes.[23] Pitsillou E, Bresnehan S M, Kagarakis E A, et al. The cell of major depressive disorder: towards a unified model for understanding clinical depression[J]. Mol Biol Rep, 2020, 47(1): 753-770.[24] Fries G R, Saldana V A, Finnstein J, et al. Molecular pathways of major depressive disorder converge on the synapse[J]. Mol Psychiatry,2023, 28(1): 284-297[25] 于泽芳 , 范理菊 , 尹晓玉 , 等 .新型速效抗抑郁药的研究进展 [J]. 中国临床药理学与治疗学, 2022, 27(5): 595-600.[26] Howland R H. Deuterated drugs[J]. J Psychosoc Nurs Ment HealthServ, 2015, 53(9): 13-16.[27] Anon. ACNP 61st annual meeting: poster abstracts P271-P540[J]. Neuropsychopharmacology, 2022, 47(Suppl 1): 220-370.[28] Nguyen L, Scandinaro A L, Matsumoto R R. Deuterated (d6)- dextromethorphan elicits antidepressant-like effects in mice[J]. Pharmacol Biochem Behav, 2017, 161: 30-37.美编排版：王子怡感谢您阅读《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

临床研究

2022-11-22

·PRNewswire

EmbarkNeuro Announces Initiation of Phase 2 Trial of ANC-501, a First-In-Class, V1b Receptor Antagonist for the Personalized Treatment of Depression

VILLANOVA, Pa. and OAKLAND, Calif., Nov. 21, 2022 /PRNewswire/ -- EmbarkNeuro, a neuroscience-focused biotech company formerly known as Ancora Bio that was founded in 2021 by the venture firm Aditum Bio, today announced that the first patient has been dosed in its Phase 2 trial of ANC-501, a first-in-class vasopressin 1b (V1b) receptor antagonist for the treatment of major depressive disorder (MDD). This 8-week single-arm trial will assess the efficacy of ANC-501 when added to a standard antidepressant therapy in patients with biomarker-confirmed disruption in their stress-response system. "Rates of depression and anxiety have risen dramatically since the advent of the COVID-19 pandemic, which has spurred extreme stress due to social isolation and exacerbated health concerns," said Stephen Kanes M.D., Ph.D., Chief Executive Officer of EmbarkNeuro. "As people with a history of adverse childhood experiences, toxic stress or HPA axis disruption have been the hardest hit, it is more important than ever to rethink all aspects of mental health interventions and create targeted treatments with underlying conditions in mind for patients not responsive to standard therapies. We look forward to advancing ANC-501 and providing patients with depression and measurable disruption of their HPA axis with a treatment option. Our new name, EmbarkNeuro, represents our enthusiasm as we embark on the exploration of new pathways for the treatment of brain health disorders." The multi-center, open-label Phase 2 clinical trial is designed to evaluate the safety, tolerability, and efficacy of orally administered ANC-501 50mg over 8 weeks. The trial will enroll individuals aged 18-65 who are currently depressed and for whom standard treatments have not been effective. Patients with moderate to severe MDD who have confirmed baseline cortisol level elevations are eligible to participate. The primary efficacy endpoint is change from baseline at the end of 8 weeks of treatment using the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Participants will be followed for safety assessments for an additional 8 weeks following completion of dosing. For more information about the trial, please visit www.clinicaltrials.gov (identifier NCT05439603). A double-blind placebo-controlled trial of ANC-501 in patients with depression is planned for 2023 based on the outcome of this initial Phase 2 trial. ANC-501 is an investigational compound and not approved by the U.S. Food and Drug Administration (FDA) or any other regulatory authority. About Major Depressive Disorder (MDD) Major depressive disorder (MDD) is a common condition affecting over 20 million U.S. residents annually causing social, occupational, and educational impairment, along with depressed mood or loss of interest or pleasure in daily activities. The hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in managing the body's response and adaption to stress. The peptide hormone vasopressin acting through the vasopressin 1b (V1b) receptors is a key regulator of the body's stress response. About EmbarkNeuro EmbarkNeuro, formerly known as Ancora Bio, is focused on bringing important new personalized treatments to patients with mental health disorders. Rates of major depression are rapidly rising, much of this attributable to the dramatic increase in stress brought on by the COVID-19 pandemic. The company is identifying depressed individuals with a potential biomarker linked to the stress response system (elevated cortisol) and developing ANC-501 as a new treatment specifically for these patients. For more information about EmbarkNeuro, please visit https://embarkneuro.com/.

临床2期

2021-06-30

·Endpoints

Joe Jimenez and Mark Fishman sign up their 5th drug candidate — and they have another big target in their crosshairs

Ex-Novartis chief Joe Jimenez and his longtime colleague Mark Fishman have now ramped up their 5th biotech sub at the upstart Aditum. And once again, they’re tackling a big, tough market. The new outfit is called Ancora Bio, and its drug is a selective vasopressin 1b receptor — V1b — antagonist from Taisho Pharmaceutical that will roll ahead under a new code name: ANC-501. Evidently this is the same depression drug that Taisho tested in a recent Phase II clinical study. Some numbers trended in its favor compared to a placebo but fell short of statistical significance — just one in a long series of failures for major depression.

100 项与 Brezivaptan 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
重度抑郁症	临床2期	美国	Taisho Pharmaceutical R&D, Inc.	2017-07-03
焦虑症	药物发现	日本	Taisho Pharmaceutical Co., Ltd.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05439603 (CTgov)	临床2期	重度抑郁症	15	ANC-501	鑰獵襯膚築艱醖艱願衊(鏇齋鬱製製鏇夢鑰鹹鏇) = 蓋醖願淵憲夢積簾範繭簾鹽範糧鏇醖顧願範餘 (製範鹽夢醖蓋願鹽鹽鹽, 10.09) 更多	-	2024-12-31
NCT03093025 (CTgov)	临床2期	重度抑郁症	51	TS-121 10 mg (TS-121 10mg)	鏇網鬱觸鬱觸願淵繭壓(構憲醖廠餘窪窪醖憲構) = 艱淵廠範鏇鹽膚遞願獵鬱選積憲鬱築選鹹範積 (製簾積鏇獵膚夢顧選窪, 夢網襯願願窪鏇鬱壓積 ~ 壓顧鑰觸襯製餘願壓鏇) 更多	-	2019-12-09
NCT03093025 (CTgov)	临床2期	重度抑郁症	51	TS-121 50 mg (TS-121 50mg)	鏇網鬱觸鬱觸願淵繭壓(構憲醖廠餘窪窪醖憲構) = 製網壓鹹糧願淵夢繭遞鬱選積憲鬱築選鹹範積 (製簾積鏇獵膚夢顧選窪, 繭夢選廠網繭願艱壓餘 ~ 簾憲觸鬱淵壓糧築鬱廠) 更多	-	2019-12-09