Does the antidepressant-like effect of mirtazapine and venlafaxine differ between male and female rats? / ¿El efecto de tipo antidepresivo de la mirtazapina y la venlafaxina difiere entre ratas macho y hembra?

Abstract Introduction Depression is a global health problem with nearly 350 million people affected, mainly women. However, nowadays a rising amount of men are being diagnosed. This makes necessary the screening of new treatment options that are effective in women as well as in men. Objective To analyze if the administration of mirtazapine and venlafaxine to male and female rats shows a sex-related antidepressant-like effect, and the possible associated neurochemical mechanisms. Method Mirtazapine (40 mg/kg) or venlafaxine (60 mg/kg) were administered subchronically to young adult male and female (ovariectomized and steroid-primed) rats, and their antidepressant-like effects were evaluated using the forced swim test (FST). The active behaviors, swimming and climbing, were also analyzed. Results a) mirtazapine and venlafaxine reduced immobility in the FST in males and females; b) both antidepressants increased climbing and swimming in male rats; c) in female rats, mirtazapine and venlafaxine only increased swimming. Discussion and conclusion In males, the effects of mirtazapine and venlafaxine seem to be produced by the activation of the serotonergic and noradrenergic systems. Conversely, estradiol might be modulating the mechanisms of action of both antidepressants in females producing only an increased swimming and suggesting the participation of the serotonergic system.

Resumen Introducción La depresión es un trastorno psiquiátrico que representa un problema de salud mundial. Afecta a cerca de 350 millones de personas, predominantemente mujeres. Sin embargo, algunos reportes indican que su incidencia en hombres está aumentando, por lo que es necesario buscar opciones de tratamiento que sean igualmente efectivas en ambos sexos. Objetivo Analizar si existen diferencias relacionadas con el sexo en el efecto de tipo antidepresivo de la mirtazapina y la venlafaxina, y considerar los posibles mecanismos neuroquímicos involucrados. Método se administraron mirtazapina (40 mg/kg) o venlafaxina (60 mg/kg) en esquema subcrónico a grupos independientes de ratas macho y hembra ovariectomizadas tratadas con estradiol y progesterona. Se evaluaron el efecto tipo antidepresivo y las conductas activas (nado y escalamiento) utilizando la prueba de nado forzado (PNF). Resultados a) tanto la mirtazapina como la venlafaxina redujeron la inmovilidad en la PNF en machos y hembras; b) ambos antidepresivos incrementaron las conductas activas en machos; c) en hembras, la mirtazapina y la venlafaxina produjeron un aumento del nado, pero no modificaron el escalamiento. Discusión y conclusión En machos, los efectos de la mirtazapina y la venlafaxina en la PNF se deben a su acción sobre los sistemas serotonérgico y noradrenérgico; en cambio, en hembras sólo se modifica la conducta de nado, lo que sugiere que el estradiol modula las acciones de ambos antidepresivos sobre el sistema serotoninérgico.

The combination of mirtazapine plus venlafaxine reduces immobility in the forced swim test and does not inhibit female sexual behavior.

INTRODUCTION: Depression is a psychiatric disorder with higher incidence in women. Among the most common and less investigated adverse effects of antidepressants are the female sexual dysfunctions. Up to one third of the patients fail to respond to antidepressants; therefore, more treatment alternatives are necessary. The combination of mirtazapine plus venlafaxine, known as "California Rocket Fuel" has shown to be an option for treatment-resistant depression. However, there are no reports of the effects of this combination in animal models and its action on female sexual behavior is unknown. AIM: To analyze the effect of mirtazapine and venlafaxine alone or combined -given at doses with actions on the forced swim test- on female rat sexual behavior. METHODS: Mirtazapine (10, 20 or 40 mg/kg) and venlafaxine (15, 30 or 60 mg/kg) or their combinations (2.5/3.75, 5/7.5, 10/15 and 20/30 mg/kg mirtazapine and venlafaxine, respectively) were injected to sexually receptive female rats. We evaluated their effect on the forced swim test (FST). The doses that reduced immobility were tested on proceptivity and receptivity. RESULTS: Mirtazapine (40 mg/kg) and venlafaxine (60 mg/kg), administered alone, or combined (mirtazapine, 5, 10 and 20 mg/kg plus venlafaxine, 7.5, 15 and 30 mg/kg) reduced immobility, but affected motor activity. However, the reduced locomotion after the lowest combination (5/7.5 mg/kg) was smaller. Mirtazapine at 40 mg/kg reduced proceptivity and receptivity, while 60 mg/kg venlafaxine only decreased proceptivity. The combination of 5/7.5 mg/kg mirtazapine and venlafaxine did not affect female sexual behavior. CONCLUSIONS: Mirtazapine and venlafaxine exerted an effect in the FST, which was also evident when sub-effective doses of both antidepressants were combined. This combination also lacked adverse effects on female sexual behavior. The results suggest that "California Rocket Fuel" could be an effective antidepressant therapy with no adverse sexual effects in women.