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

ABSTRACT: 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-HT_1B 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-HT_1B 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-HT_2A 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-HT_1B receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT_1B receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.

SUBMITTER: Yang KC

PROVIDER: S-EPMC6784989 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Yang Kai-Chun KC Stepanov Vladimir V Amini Nahid N Martinsson Stefan S Takano Akihiro A Bundgaard Christoffer C Bang-Andersen Benny B Sanchez Connie C Halldin Christer C Farde Lars L Finnema Sjoerd J SJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190619 10

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 ...[more]

PMID: 31216565

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Project description:UnlabelledStudies in rodents indicate that the disruption of P-glycoprotein (P-gp) function increases drug distribution into the developing fetus and organs such as the brain. To simultaneously and serially evaluate the effect of P-gp activity and inhibition on the tissue distribution of drugs in a more representative animal model, we tested the feasibility of conducting whole-body PET of the pregnant nonhuman primate (Macaca nemestrina). We used (11)C-verapamil as the prototypic P-gp substrate and cyclosporine A (CsA) as the prototypic inhibitor.MethodsFour pregnant macaques (gestational age, 145-159 d; gestational term, 172 d) were imaged after the intravenous administration of (11)C-verapamil (30-72 MBq/kg) before and during intravenous infusion of CsA (12 or 24 mg/kg/h, n = 2 each). The content of verapamil and its metabolites in plasma samples was determined using a rapid solid-phase extraction method. The plasma and tissue time-radioactivity concentration curves of (11)C were integrated over 0-9 min after each verapamil injection. The tissue or arterial plasma area under the time-concentration curve (AUC(tissue)/AUC(plasma)) served as a measure of the tissue distribution of (11)C radioactivity. CsA effect on (11)C radioactivity distribution was interpreted as P-gp inhibition. The change in the fetal liver AUC ratio served as a reporter of placental P-gp inhibition.ResultsCsA effect on tissue distribution of (11)C radioactivity (AUC ratios) did not increase with the mean blood concentration of CsA, indicating a near-maximal P-gp inhibition. CsA increased maternal brain and fetal liver distribution of (11)C radioactivity by 276% +/- 88% (P < 0.05) and 122% +/- 75% (P < 0.05), respectively. Changes in other measured tissues were not statistically significant.ConclusionThese data demonstrate for the first time, to our knowledge, the feasibility of simultaneous, serial, noninvasive imaging of P-gp activity and inhibition in multiple maternal organs and the placenta in the nonhuman primate. Our findings, consistent with previous data in rodents, indicate that the activity of P-gp in the placenta and the blood-brain barrier is high and that the inhibition of P-gp facilitates drug distribution across these barriers.

Dataset Information

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

Publications

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

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