Identification of a novel off-target of paroxetine: Possible role in sexual dysfunction induced by this SSRI antidepressant drug

Paroxetine is a widely used antidepressant drug, usually prescribed to treat major depression disorder, anxiety, but is also common in managing chronic pain, eating disorders, some forms of headache and sleep disturbances. Antidepressants, and paroxetine in particular, are linked to side effects, and sexual dysfunction is one of the most prevalent. To explore possible mechanisms leading to this symptomatology, an unbiased approach was applied to retrieve potential paroxetine off-target proteins. A 3D proteome-wide scale in silico screening of a human and murine protein database using SPILLO-PBSS software indicated that the enzyme phenylethanolamine N-methyltransferase (PNMT), the limiting enzyme in the formation of epinephrine, also potentially interacts with paroxetine. Then, a multidisciplinary approach was applied to confirm this finding. Indeed, docking and molecular dynamics analysis and an in vitro assay indicated that paroxetine is able to inhibit PNMT, a result also confirmed in an animal model. The catecholamines norepinephrine and epinephrine are involved in sexual function, and their altered levels have been associated with erectile dysfunction. Thus, based on the fact that the PNMT enzyme is involved in epinephrine production, and that the data here reported indicate that paroxetine inhibits PNMT, a possible role of this enzyme in the sexual dysfunction reported by antidepressant users can be suggested.