Clinical implications of fluvoxamine and fluoxetine with sigma-1 receptor chaperone activity in the treatment of neuropsychiatric disorders

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are used as therapeutic drugs for a number of neuropsychiatric diseases throughout the world. Although all SSRIs act by blockading serotonin transporters, leading to elevated serotonin levels in the central nervous system (CNS), it is well known that their pharmacology is quite heterogeneous. Endoplasmic reticulum protein sigma-1 receptors represent a unique chaperone activity, and they exert a potent influence on a number of neurotransmitter systems. Accumulating evidence suggests that sigma-1 receptors play a role in the pathophysiology of neuropsychiatric and cardiovasular diseases, as well as in the mechanisms of some SSRIs. Among the SSRIs, the order of affinity for sigma-1 receptors is as follows: fluvoxamine > sertraline > fluoxetine > escitalopram > citalopram » paroxetine. In cell culture systems, some SSRIs (e.g., fluvoxamine, fluoxetine and escitalopram) potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, and these effects can be antagonized by the selective sigma-1 receptor antagonist, NE-100. Furthermore, fluvoxamine, but not paroxetine or sertraline, improved phencyclidine-induced cognitive impairment in mice, and again, this effect could be antagonized by NE-100. Several clinical studies have found that fluvoxamine may offer beneficial effects in patients with neuropsychiatric disorders. In this chapter, the authors will discuss the role of sigma-1 receptors in the mechanistic action of some SSRIs and new clinical implications for SSRIs with potent sigma-1 receptor chaperone activity. © 2015 by Nova Science Publishers, Inc. All rights reserved.