Neuropharmacology of Paroxetine

Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with some neuropharmacologic properties unique among this class of compounds. Early in vitro studies demonstrated the potency of paroxetine at inhibiting 5-HT uptake in rat synaptosomes. Paroxetine has also been shown to be a potent and selective inhibitor of the human serotonin transporter (SERT) and has recently been demonstrated to have moderate affinity for the norepinephrine transporter (NET). Because of its affinity and in vitro selectivity, tritiated paroxetine is now widely used as a marker for SERT in laboratory settings, and its use has advanced our understanding of neurotransmitter function in the brain and periphery. The in vivo pharmacologic properties of paroxetine are well characterized, especially following acute administration; however, the pharmacologic effects of chronically administered paroxetine remain an active area of study. Paroxetine administration in laboratory animals has been associated with decreased SERT density and function, maintenance of normal firing rates and 5-HT release, and increased activation of postsynaptic 5-HT receptors. Using a novel ex vivo assay, it has been demonstrated that paroxetine exhibits dose-related inhibition of the NET in patients treated for depression. At usual clinical doses (20 mg/d), paroxetine is a potent and selective inhibitor of SERT; however, at higher doses (≥40 mg/d), it can exhibit marked NET inhibition. The application of these findings of in vivo NET inhibition by paroxetine in the treatment of mood and anxiety disorders will be informed by further clinical studies.