P.3.026 The impact of antipsychotic drugs in depression: a role for adult neurogenesis?

Abstract

Purpose: Antidepressants acting via inhibition of the serotonin (5-HT) transporter (SERT) inhibit sexual behavior. Vortioxetine, an antidepressant with a multimodal mechanism of action, is an inhibitor of the SERT, a 5-HT3A, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1A receptor agonist and a 5-HT1B receptor partial agonist. Since modulating 5-HT receptor subtypes (e.g., 5-HT1A, 5-HT1B receptors) and the transporter may affect sexual function differently, we compared the effects of vortioxetine and a selective serotonin reuptake inhibitor (SSRI), paroxetine, on the sexual behavior of male rats. In an effort to dissect vortioxetine pharmacology, the effects of acute and chronic modulation of several serotonin receptors (5-HT1A, 5-HT1B and 5-HT3) were also studied in the same behavior paradigm. Method: Young adult male Wistar rats received 5 weekly trainings on copulation with a female that was in pharmacologically induced estrus. Low performers were excluded from the study. Mating sessions were video taped and manually scored on measures of male rat sexual behavior: latency and number of ejaculations, mounts and intromissions. The effects of vortioxetine (1 and 10mg/kg/day), paroxetine (10mg/kg/day), flesinoxan (5-HT1A agonist, 2.5mg/kg twice daily), CP-94253 (5-HT1B agonist, 5mg/kg daily), ondansetron (5-HT3 antagonist, 1mg/kg twice daily) and vehicle were compared immediately after the first dosing and after 1 and 2 weeks of repetitive dosing. As the affinity of vortioxetine for the rat 5-HT1A receptor is approximately 10-fold lower than for the human 5-HT1A receptor, vortioxetine was also tested in the presence of flesinoxan (2.5mg/kg twice daily) to mimic the human level of 5-HT1A receptor activation. Vortioxetine was dosed via the food; all other compounds were administered via subcutenous injections. Antidepressant exposures were determined as SERT occupancy using ex vivo autoradiography. Repeated measures and one-way ANOVA were performed, followed by individual t-tests. P< 0.05 was considered statistically significant. Results: Neither vortioxetine nor vortioxetine plus flesinoxan affected sexual behavior in male rats, whereas 2 weeks of paroxetine impaired sexual behavior significantly in several measures. Vortioxetine, 1 and 10mg/kg, corresponded to 50 and 87% SERT occupancy, which matched occupancies seen at clinical doses (5−20mg/day), as shown in human PET studies. Paroxetine produced approximately 90% SERT occupancy. Flesinoxan enhanced sexual function in male rats after acute and 1-week dosing, but not after 2 weeks’ treatment. Acute, 1-week and 2-week CP-94235 treatment significantly impaired sexual behavior. Ondansetron impaired ejaculation frequency only after 2 weeks of treatment. Conclusion: Vortioxetine at clinically relevant levels of SERT occupancy did not affect male rat sexual performance. Studies of selective compounds acting on the 5-HT receptor subtypes targeted by vortioxetine showed either improvement or deterioration of sexual performance in male rats. Therefore, the apparent neutral effect on sex performance of vortioxetine in this animal model is likely to be the result of a summation of simultaneous modulation of multiple 5-HT receptors plus SERT inhibition. Disclosure statement: This abstract is financially supported by a grant from Lundbeck Research USA.