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.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 4
- Modulating tonic NMDA receptor currents: mechanistic insights into ketamine, esketamine, and dextromethorphan for major depressive disorder and implications for the discovery and development of investigational agents. Expert Opinion on Therapeutic Targets January 28, 2026
- Synaptic Plasticity-Intrinsic Excitability and Antidepressant Discovery. Biomedicines June 1, 2026
- The Serotonin 2B (5‐ HT2B ) Receptor: A Narrative Review of Preclinical and Clinical Evidence on the Safety Considerations and Therapeutic Potential for the Treatment of Depression Clinical Pharmacology & Therapeutics May 28, 2026
- Abuse liability of dextromethorphan and its combinatory formulation dextromethorphan/bupropion: a pharmacologic perspective. Expert Opinion on Drug Metabolism & Toxicology 2026
Cites 5
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Dextromethorphan-Bupropion for the Treatment of Depression: A Systematic Review of Efficacy and Safety in Clinical Trials. CNS Drugs October 1, 2023
- Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). The Journal of Clinical Psychiatry May 30, 2022
- Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. American Journal of Psychiatry May 18, 2022
- Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo. European Neuropsychopharmacology April 2012