Naomi Xiao, Liyang Yin, Kayla M Teopiz, Angela T H Kwan, Gia Han Le, Sabrina Wong, Kyle Valentino, Hayun Choi, Joshua D Rosenblat, Roger Ho, Serene Lee, Roger S McIntyre
{"title":"The sigma-1 receptor: a mechanistically-informed therapeutic target for antidepressants.","authors":"Naomi Xiao, Liyang Yin, Kayla M Teopiz, Angela T H Kwan, Gia Han Le, Sabrina Wong, Kyle Valentino, Hayun Choi, Joshua D Rosenblat, Roger Ho, Serene Lee, Roger S McIntyre","doi":"10.1080/14728222.2025.2500424","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The mechanism of action of antidepressants is not fully ascertained. In addition to monoamines, disparate other effectors are also implicated in the molecular and cellular effects of chronic stress including neurogenesis, neurodifferentiation, and neuroplasticity. Evidence suggests sigma-1 receptors (S1Rs) as a putative target and possible mediator of antidepressant activity.</p><p><strong>Areas covered: </strong>Data from preclinical and clinical trials was synthesized from inception to August 2024. Results showed that S1Rs regulate neurotransmitter availability and release (e.g. monoamines, glutamate), and influence intracellular Ca<sup>2+</sup> levels as well as immune inflammatory responses. The introduction of the N-Methyl-D-aspartic Acid (NMDA) antagonist/S1R agonist dextromethorphan-bupropion in August of 2022 represented the first time the Food and Drug Administration (FDA) permitted language that the hypothesized mechanism of an antidepressant involved activity at S1Rs. We also describe the physiology, pathophysiology, and function of S1Rs.</p><p><strong>Expert opinion: </strong>Sigma-1 modulation is relevant to the mechanism of action of agents currently FDA-approved in major depressive disorder (MDD) (e.g. dextromethorphan-bupropion). Modulating sigma-1 systems is fit for purpose as it relates to future therapeutic discoveries and development in depressive and other mental disorders. Whether sigma-1 modulation is uniquely relevant to targeting dimensions of psychopathology that are more difficult to treat (i.e. anhedonia) awaits determination.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"1-15"},"PeriodicalIF":4.6000,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert Opinion on Therapeutic Targets","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14728222.2025.2500424","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: The mechanism of action of antidepressants is not fully ascertained. In addition to monoamines, disparate other effectors are also implicated in the molecular and cellular effects of chronic stress including neurogenesis, neurodifferentiation, and neuroplasticity. Evidence suggests sigma-1 receptors (S1Rs) as a putative target and possible mediator of antidepressant activity.
Areas covered: Data from preclinical and clinical trials was synthesized from inception to August 2024. Results showed that S1Rs regulate neurotransmitter availability and release (e.g. monoamines, glutamate), and influence intracellular Ca2+ levels as well as immune inflammatory responses. The introduction of the N-Methyl-D-aspartic Acid (NMDA) antagonist/S1R agonist dextromethorphan-bupropion in August of 2022 represented the first time the Food and Drug Administration (FDA) permitted language that the hypothesized mechanism of an antidepressant involved activity at S1Rs. We also describe the physiology, pathophysiology, and function of S1Rs.
Expert opinion: Sigma-1 modulation is relevant to the mechanism of action of agents currently FDA-approved in major depressive disorder (MDD) (e.g. dextromethorphan-bupropion). Modulating sigma-1 systems is fit for purpose as it relates to future therapeutic discoveries and development in depressive and other mental disorders. Whether sigma-1 modulation is uniquely relevant to targeting dimensions of psychopathology that are more difficult to treat (i.e. anhedonia) awaits determination.
前言：抗抑郁药的作用机制尚未完全确定。除了单胺，其他不同的效应器也涉及慢性应激的分子和细胞效应，包括神经发生、神经分化和神经可塑性。有证据表明sigma-1受体（S1Rs）是抗抑郁活性的假定靶点和可能的中介。涵盖领域：从开始到2024年8月，临床前和临床试验数据进行了综合。结果表明，S1Rs调节神经递质可用性和释放（如单胺、谷氨酸），并影响细胞内Ca2+水平和免疫炎症反应。2022年8月，n-甲基- d -天冬氨酸（NMDA）拮抗剂/S1R激动剂右美沙芬-安非他酮的引入，标志着美国食品和药物管理局（FDA）首次允许这种抗抑郁药的假设机制涉及S1R活性。我们还描述了S1Rs的生理、病理生理和功能。专家意见：Sigma-1调节与目前fda批准的治疗重度抑郁症（MDD）的药物（如右美沙芬-安非他酮）的作用机制有关。调节sigma-1系统符合目的，因为它关系到抑郁症和其他精神障碍的未来治疗发现和发展。sigma-1调节是否与更难治疗的精神病理（即快感缺乏）的靶向维度有独特的关系尚待确定。
期刊介绍：
The journal evaluates molecules, signalling pathways, receptors and other therapeutic targets and their potential as candidates for drug development. Articles in this journal focus on the molecular level and early preclinical studies. Articles should not include clinical information including specific drugs and clinical trials.
The Editors welcome:
Reviews covering novel disease targets at the molecular level and information on early preclinical studies and their implications for future drug development.
Articles should not include clinical information including specific drugs and clinical trials.
Original research papers reporting results of target selection and validation studies and basic mechanism of action studies for investigative and marketed drugs.
The audience consists of scientists, managers and decision makers in the pharmaceutical industry, academic researchers working in the field of molecular medicine and others closely involved in R&D.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
