THE INFLUENCE OF DULOXETINE ON DETRUSOR OVERACTIVITY INDUCED BY DEPRESSION
A. WROBEL 1, E. RECHBERGER 2, T. RECHBERGER3, K. A. SKORUPSKA 4, P. MIOTLA 5;
12nd Gyneacology Department, Med. Univ. in Lublin, Lublin, Poland, 2Med. Univ. of lublin, lublin, Poland, 3II Dept. of Gynecology Med. Univ., Lublin, Poland, 42nd Dept. of Gynecology UM in Lublin, Lublin, Poland, 52nd Dept. of Gynecology, Med. Univ., Lublin, Poland.
Introduction: OAB patients are frequently diagnosed with various mental disorders, including depression. The presence of such a link was confirmed by numerous epidemiological tests. The CRF is considered a primary initiator of changes leading to depression. The brain regions with high concentration of CRF1 and CRF2 receptors, such as Barrington’s nucleus in the brainstem amygdala, the prefrontal cortex or the hippocampus, play an important role in the etiopathogenesis of depression and in voiding control. CRF lowered the threshold of the afferent impulsation of the voiding reflex and increased the contractibility of the bladder detrusor, whose level increased in response to bladder distention. CRF1 selective antagonists were found to have a reducing effect on detrusor overactivity (DO). Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine (SNRI) and has been approved for the treatment of major depression and SUI. Duloxetine increased bladder capacity through the increase of urethral sphincter muscle activity without affecting the micturition phase. It modulates the activity of the motoneurons of Onuf’s nucleus, and prevents accidental bladder voiding. Duloxetine can inhibit DO development and modulate sensory processing, which would justify its use in OAB treatment.
Objective: The aim of this study was to assess the effectiveness of duloxetine in an animal model of DO induced by depression.
Methods: The following drugs were used: - 13-cis-retinoic acid (13-cis-RA)- injected intraperitoneally in a dose of 1 mg/kg/day for a period of 6 weeks, at a volume of 1 ml/kg of body weight, - Duloxetine hydrochloride- administered intravenously in a single dose of 1 mg/kg at a volume of 1 ml/kg of body weight (1). After 6 weeks of 13-cis-RA administration, cystometric studies were performed in order to assess the 13-cis-RA impact on the micturition cycle and to examine the influence of duloxetine on the cystometric parameters modified by retinoid treatment. Next, blood samples were collected and hypothalamus and amygdala were isolated in order to examine the level of 13-cis-RA and CRF.
Results: A single administration of duloxetine did not cause any significant cystometric changes when compared to the control group. The 13-cis-RA administration led to changes to cystometric parameters characteristic of DO. An increase was observed in: BP, TP, MVP, DOI, ANVC and FNVC, while a decrease was noted in VV, VT, ICI, BC and VTNVC. The retinoid, in turn, did not cause any changes to PVR, VE, BCD and RT. Intravenous administration of duloxetine to animals previously treated with 13-cis-RA led to a decrease in DOI, ANVC and FNVC and to an increase in BC and VTNVC. After the administration of SNRI, no statistically significant changes were observed in such parameters as BP, TP, MVP, PVR, VT, VE, ICI, BCD and RT (Table 1). The plasma level of the retinoid in the 13-cis-RA group was 0.58 ± 0.021 μg/ml, while in the control group the plasma samples contained essentially no measurable 13-cis-RA (Table 2). Single dose of duloxetine had a statistically significant impact on the CRF level in both the examined brain structures and the plasma. The animals which had been receiving 13-cis-RA had an increased level of CRF in hypothalamus, amygdala and plasma. The administration of duloxetine to rats previously treated with 13-cis-RA caused the CRF level to decrease in the hypothalamus, amygdala and plasma.
Conclusions: Duloxetine seems to be an interesting option in OAB wet treatment, especially in patients with coexisting depression
References: 1. All procedures were conducted in accordance with the European Communities Council Directive of 22 September 2010 (2010/63/EU) and were approved by the Local Ethics Committee