The sigma–1 receptor: a mechanistically–informed therapeutic target for antidepressants

作者：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 M. L. Lee, Roger S. McIntyre · 发表于：Expert Opinion on Therapeutic Targets · 年份：2025 · DOI：10.1080/14728222.2025.2500424 · 被引用次数：5 · 研究领域：Pharmacological Receptor Mechanisms and Effects、Tryptophan and brain disorders、Treatment of Major Depression

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: 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.