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

Expert Opin Ther Targets. 2025 Apr 29. doi: 10.1080/14728222.2025.2500424. Online ahead of print.

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 (S1R) 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 S1R 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 S1R. We also describe the physiology, pathophysiology, and function of S1R.

EXPERT OPINION: Sigma-1 modulation is relevant to the mechanism of action of agents currently FDA-approved in major depressive disorder (MDD) (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.

PMID:40298911 | DOI:10.1080/14728222.2025.2500424