Pharmacological insights into fluvoxamine maleate: σ1 receptor agonism, multimodal mechanisms, and therapeutic repositioning.

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.