Current opinion in pharmacologySep 17, 2026

How fluvoxamine works through sigma-1 receptor activation and other actions, and its potential new medical uses

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 18, 2026

Abstract

Fluvoxamine maleate (FM) demonstrates one of the highest affinities for the sigma 1 receptor among SSRIs.

FM exhibits strong agonistic activity at the sigma 1 receptor, which may enhance protein refolding and cellular resilience.
It alleviates protein misfolding, endoplasmic reticulum stress, and neuroinflammation in various mental and neurological disorders.
Preclinical studies show FM inhibits indicators of the unfolded protein response and reinstates glutamatergic transmission.
FM's effects include stimulation of parvalbumin interneurons, leading to antipsychotic-like outcomes in schizophrenia.
It may also provide neuroprotection against ketamine-induced impairments and has potential benefits against tardive dyskinesia.
Fluvoxamine's effectiveness is linked to its sigma 1 receptor activity, particularly in disorders related to endoplasmic reticulum stress.

Simplified

Fluvoxamine maleate (FM) is a selective serotonin reuptake inhibitor (SSRI) that has attracted increased attention owing to its strong agonistic activity at the sigma 1 receptor (σ1R). This review consolidates the current understanding of its processes highlighting σ1R-mediated chaperone activity in the endoplasmic reticulum (ER), which alleviates protein misfolding, ER stress, and neuroinflammation in mental and neurological illnesses. Fluvoxamine demonstrates one of the highest affinities for σ1R among SSRIs, exceeding those of sertraline and fluoxetine, via dissociating σ1R from BiP chaperones to improve protein refolding and cellular resilience. Preclinical experiments illustrate its inhibition of unfolded protein response indicators, reinstatement of glutamatergic transmission, and stimulation of parvalbumin interneurons, resulting in antipsychotic-like effects in schizophrenia and neuroprotection against ketamine-induced impairments. In addition to serotonin reuptake inhibition, fluvoxamine influences inflammation, apoptosis, and extracellular matrix dynamics. Supplementary activities include advantages against tardive dyskinesia and cognitive improvement in depression by mitigating stress induced neuronal atrophy. Repurposing initiatives underscore fluvoxamine's potential beyond obsessive compulsive disorder (OCD) and depression. σ1R agonism is fundamental to its effectiveness in disorders caused by ER stress, such as schizophrenia and tardive dyskinesia, and in neuropsychiatric sequelae associated with protracted COVID. Clinical translation encounters obstacles in dose optimization and σ1R selectivity; yet, current studies highlight its multimodal efficacy in neurodegeneration, fibrosis, and psychopharmacology.

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How fluvoxamine works through sigma-1 receptor activation and other actions, and its potential new medical uses

Abstract

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