Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 44; no. 10; pp. 1706 - 1713
• Main Authors: Yang, Kai-Chun, Stepanov, Vladimir, Amini, Nahid, Martinsson, Stefan, Takano, Akihiro, Bundgaard, Christoffer, Bang-Andersen, Benny, Sanchez, Connie, Halldin, Christer, Farde, Lars, Finnema, Sjoerd J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2019; Springer International Publishing
• Subjects: Animals; Antidepressants; Benzopyrans; Benzylamines; Brain; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Citalopram; Citalopram - metabolism; Citalopram - pharmacology; Dorsal raphe nucleus; Dorsal Raphe Nucleus - diagnostic imaging; Dorsal Raphe Nucleus - drug effects; Dorsal Raphe Nucleus - metabolism; Dosage; Drug development; Emission analysis; Female; Macaca mulatta; Medicin och hälsovetenskap; Morpholines; Phenethylamines; Piperazines; Positron emission tomography; Raphe nuclei; Receptor, Serotonin, 5-HT1B - metabolism; Receptor, Serotonin, 5-HT2A - metabolism; Serotonin; Serotonin S1 receptors; Serotonin S2 receptors; Serotonin uptake inhibitors; Serotonin Uptake Inhibitors - metabolism; Serotonin Uptake Inhibitors - pharmacology; Vortioxetine - metabolism; Vortioxetine - pharmacology
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-019-0442-4

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 [ C]AZ10419369 to the 5-HT receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of vortioxetine was determined by [ C]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 [ C]AZ10419369. The 5-HT 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 [ C]Cimbi-36 to the 5-HT receptor, which has comparable sensitivity to 5-HT release as [ C]AZ10419369 binding. In conclusion, at clinically relevant doses, vortioxetine induced larger reductions in [ C]AZ10419369 binding than citalopram. These observations suggest that vortioxetine binds to the 5-HT receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.