The sigma–1 receptor: a mechanistically–informed therapeutic target for antidepressants
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: 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.
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DXM-bupropion operates through a broader multimodal profile: weak NMDA antagonism is complemented by sigma 1 receptor activation and dopamine transporter inhibition.
“Weak NMDA antagonism is complemented by sigma 1 receptor activation and dopamine transporter inhibition, shaping excitability, stress resilience, and neurotrophic tone alongside glutamatergic mechanisms [57,58,59].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [57]
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- Authors
- Xiao, N., Yin, L., Teopiz, K. M., Kwan, A. T. H., Le, G. H., Wong, S., Valentino, K., Choi, H., Rosenblat, J. D., Ho, R., Lee, S., & McIntyre, R. S.
- Affiliations
- Queen's University (CA)
- Brain and Cognition Discovery Foundation (CA)
- University of Ottawa (CA)
- University Health Network (CA)
- United States Department of Veterans Affairs (US)
- National University of Singapore (SG)
- University of Toronto (CA)
- Corresponding author
- McIntyre, Roger S.
- ORCID
- Venue
- Expert Opinion on Therapeutic Targets
- Publisher
- Informa UK Limited
- Published
- 2025-05-06
- Volume
- 29
- Issue
- 6
- Pages
- 345-359
- ISSN
- 1472-8222 (ISSN-L)
- 1744-7631
- OpenAlex
- W4409922316
- Cited by
- 6
- References
- 80
- Citations by year
- 2026: 5 · 2025: 1
- FWCI
- 0.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Expert Opinion on Therapeutic Targets (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- sigma-1 receptor, antidepressants, major depressive disorder, mechanism of action, chronic stress, neuroplasticity, neurogenesis, neuronal differentiation, anhedonia, immune-inflammatory response, NMDA receptor antagonists
- MeSH terms
- Sigma-1 Receptor, Animals, Antidepressive Agents, Depression, Humans, Receptors, sigma, Molecular Targeted Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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