LAUSR

Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of vortioxetine by comparing its effect to the SSRI citalopram on the binding of [11C]AZ10419369 to the 5-HT1B receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of vortioxetine was determined by [11C]MADAM PET measurements before and after administration of vortioxetine (0.1–3.0 mg/kg) and data were used to confirm clinically relevant dosing in subsequent PET measurements with [11C]AZ10419369. The 5-HT1B receptor binding was significantly decreased after 0.3 mg/kg of citalopram in the dorsal raphe nucleus (5%), as well as after 0.3 mg/kg of vortioxetine in six brain regions (~25%) or 1.0 mg/kg of vortioxetine in all 12 examined regions (~48%). Moreover, there was no effect of 1.0 mg/kg of vortioxetine on the binding of [11C]Cimbi-36 to the 5-HT2A receptor, which has comparable sensitivity to 5-HT release as [11C]AZ10419369 binding. In conclusion, at clinically relevant doses, vortioxetine induced larger reductions in [11C]AZ10419369 binding than citalopram. These observations suggest that vortioxetine binds to the 5-HT1B receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT1B receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.