The sigma-1 receptor: a mechanistically-informed therapeutic target for antidepressants.
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
Expert Opinion on Therapeutic Targets June 1, 2025 DOI: 10.1080/14728222.2025.2500424 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Ketamine |
| Keywords | Sigma-1 receptor Anhedonia Cognition Dextromethorphan Glutamate #depression-treatment depression therapy Mood disorders #neuroscience brain science Neurobiology Neural pathways #antidepressants ssris Mood medication Bup |
| Citations | 5 |
| Key findings | Sigma-1 receptors regulate neurotransmitter systems and immune responses, and their modulation is relevant to the mechanism of action of the FDA-approved antidepressant dextromethorphan-bupropion. |
Abstract
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. 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. 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.