The influence of duloxetine on detrusor overactivity in rats with depression induced by 13-cis-retinoic acid

Patients with various clinical types of urinary incontinence are frequently diagnosed with mental disorders including depression. Although the putative link between such urinary tract malfunction was first described in 1964 [1], probably the first to speculate on common neurological pathways for depression and detrusor overactivity (DO) leading to both wet and dry overactive bladder (OAB) were Steers and Lee [2]. Indeed some data suggest that depression might be associated with OAB syndrome [3], but very few studies have focused on OAB patients with clinically confirmed psychiatric disorders [4, 5]. Epidemiological studies have indicated that such a link may exist. It has been demonstrated that patients with OAB have significantly worse results on the Centre of Epidemiological Studies Depression (CES-D) and quality of sleep scales [6], as well as on the Short Form Health Survey (SF-36) quality of life scale. A positive correlation has been found between depression and the development of the first symptoms of OAB. It has been suggested that depression, as assessed with the Geriatric Depression scale, is a risk factor for OAB [7]. Of patients diagnosed with depression, 13% also had symptoms of stress urinary incontinence (SUI) and 42% had symptoms of OAB or mixed urinary incontinence (MUI), and as many as 60% of patients with idiopathic urge incontinence had a history of depression or a Beck’s Depression Inventory score of >12.

Corticotropin-releasing factor (CRF) is considered a primary initiator of changes leading to depression. Its level increases especially in the paraventricular nucleus of the hypothalamus, the central nucleus of the amygdala, and Barrington’s nucleus, the pontine micturition centre. It displays strong psychotropic properties, predominantly as depressive reactions. Preclinical studies have revealed that CRF induces depressive reactions by increasing the immobility time in forced swim tests. The CRF₁ receptor antagonists show, in turn, antidepressant properties [8]. In forced swim tests the reduction in passive (immobility) behaviour is interpreted as an antidepressant-like effect [9]. Clinical trials have confirmed that patients with depression have significantly increased CRF levels in their cerebrospinal fluid. Post-mortem examinations have also revealed elevated CRF concentrations in the hypothalamus and an increase in the number of CRF-releasing neurons located in the paraventricular nucleus of the hypothalamus.

The effects of CRF are mediated by CRF₁ and CRF₂ receptors. Brain regions characterized by high concentrations of these receptors, such as Barrington’s nucleus in the brainstem amygdala, the prefrontal cortex and the hippocampus, play an important role, not only in the aetiopathogenesis of depression but also in voiding control. The neurons of Barrington’s nucleus, which project to the bladder motoneurons, are considered the switch that initiates the descending limb of the micturition reflex. There is some evidence suggesting that high CRF expression of the neurons of Barrington’s nucleus is an important factor regulating bladder detrusor function. It has been found that CRF lowers the threshold of the afferent impulsation of the voiding reflex and increases the contractile activity of the detrusor muscle, whose levels increase in response to bladder distension. In vivo cystometric tests have confirmed the excitatory effects of CRF on micturition [10]. CRF₁-selective antagonists have been found to have a reducing effect on DO. CRF has an effect on the micturition reflex, including at the level of the spinal cord. It has been shown that capsaicin, by selectively destroying afferent C-fibres, induces a decrease in CRF expression, confirming that this neurohormone is vital in the conduction of afferent impulsation from the bladder [11].

Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine (SNRI) without considerable affinity for these neurotransmitter receptors, and has been approved for the treatment of major depression and SUI. Noradrenaline and serotonin terminals are widespread in brain structures responsible for the body’s response to stress, especially in the limbic system. Deficiency in these neurotransmitters induces the development of depression, which is an indication for the administration of SNRIs such as duloxetine in patients with clinical depression [12].

It has been demonstrated that duloxetine increases bladder capacity by increasing urethral sphincter muscle activity without affecting the micturition phase [13]. By inducing an increase in serotonin and norepinephrine concentrations, it modulates the activity of the motoneurons of Onuf’s nucleus, and in this way prevents accidental bladder voiding. Only a few sources suggest that duloxetine can inhibit DO development and modulate sensory processing, which would justify its use in OAB treatment [14‐16]; however, the treatment of patients with OAB with this SNRI has not yet been indicated. At present there are no data on the use of duloxetine in the treatment of patients with depression and accompanying OAB symptoms.

These observations taken together were the basis for the experiments presented here, which had the aim of assessing the effectiveness of duloxetine in an animal model of DO induced by depression [17]. Furthermore, the effects of this SNRI on CRF levels in plasma and brain structures that play a crucial role in both the aetiopathogenesis of depression and the occurrence of OAB were also assessed.

The body weights of the rats measured weekly did not show any significant differences between the animal groups examined throughout the entire experiment. Daily monitoring of the animals confirmed that they did not manifest any signs of distress as a result of the repeated injections.

The model of depression induced by 13-cis-RA, which has also been shown to cause DO symptoms, was used in this study. Clinical trials have shown that therapeutic doses of 13-cis-RA administered to patients with severe acne can induce depressive behaviour [21]. These findings were confirmed in preclinical studies in which long-term administration of 13-cis-RA led to increases in immobility time in the forced swim test, which is consistent with increased depression-related behaviour [22]. In the experiments presented here, the rats received a dose identical to that used in acne treatment, and the determined concentrations of 13-cis-RA in plasma were analogous to those found in humans [23].

Treatment with duloxetine was found to have an antidepressant effect, as shown by significant decreases in the immobility time to the times observed in the control animals, with a simultaneous lack of effect on their locomotor activity. Treatment with duloxetine led to significant decreases in DOI, ANVC and FNVC and to increases in BC and VTNVC. Duloxetine appeared to have no effects on the other analysed parameters, namely BP, TP, MVP, PVR, VT, VE, ICI, BCD and RT. The demonstrated decrease in DOI seems to be very important, considering that an increase in this parameter is a characteristic feature of DO that allows its intensity to be determined. It is believed that DOI reflects the contraction activity of the bladder with far greater precision than ANVC, FNVC, MVP, ICI, BP or BC [18, 19]. The observed increase in VTNVC following administration of duloxetine is very interesting, because this parameter is considered a preclinical equivalent to the volume at the first involuntary detrusor contraction measured during urodynamic investigations in humans [24]. The dose used in this study was the minimally effective dose, which showed antidepressant activity in the forced swim test and simultaneously affected the cystometric parameters DOI, ANVC, FNVC, BC and VTNVC. This might suggest that duloxetine could be used in the pharmacotherapy of OAB dry, especially in patients with accompanying depression. It cannot be ruled out that higher doses administered for a longer period could effectively treat OAB wet.

Recently published studies on the link between OAB and depression were population-based epidemiological surveys and yielded conflicting results [4, 25]. In a study by Lai et al. [26], 27.5% of OAB patients had depression as confirmed by the Hospital Anxiety and Depression Scale (HADS ≥8), and affected individuals reported significantly higher HADS-D depression scores than age-matched controls. No standards for the treatment of patients with DO and accompanying depression have yet been developed, because OAB is a syndrome and does not exist as an entity. So far only one case report has been published in which the authors confirmed the efficacy of duloxetine in a female adolescent with OAB and depression [14]. It is worth noting that the patient showed resistance to antimuscarinic drugs and standard antidepressants.

The rationale for the use of duloxetine in DO stems from the direct inhibition of sensory afferents by the serotonergic system, which results in a reduction in bladder detrusor activity and a modulating effect of serotonin and noradrenaline on the micturition centres in the sacral spinal cord [27]. It has been shown that acute administration of antidepressants increases the threshold for the spinal voiding reflex, while chronic administration affects the CNS-related components of the micturition reflex, which suggests that duloxetine could inhibit bladder overactivity in patients with coexisting depression [15]. There are reports that SNRIs can induce urine retention, but this was not confirmed in our study. Duloxetine was found to have no effect on PVR.

It ha been demonstrated that duloxetine increases bladder capacity and inhibits DO induced by acetic acid, and its effects are reversed by administration of a nonselective 5-HT receptor antagonist [28]. The fact that DO induced by chemical irritation is mediated at least in part by a spinal reflex activated by nociceptive C-fibre afferents of the urinary bladder suggests the possibility that duloxetine affects not only supraspinal micturition control mechanisms but also spinal reflexes.

Clinical trials have shown that duloxetine reduces the number of frequency and urgency episodes, and improves quality of life scores, while not changing the mean voided volume [15, 16]. It has not been confirmed that it has any effects on heart rate, blood pressure or arrhythmogenic tendencies on EEG, which is significant because the majority of patients with depression and OAB are elderly. Duloxetine was found to have greater efficacy than placebo in patients with OAB due to either DO or sensory urgency, and also in patients with MUI [16, 29]. Due to the drug’s clinically proven effectiveness in the treatment of depression, it has been suggested that it should be the first-choice treatment in patients with depression and accompanying OAB [15].

In this study duloxetine was found to lower CRF levels in the hypothalamus, amygdala and plasma that were previously increased by administration of 13-cis-RA. CRF hypersecretion seems to be a common element in the aetiopathogenesis of depression and OAB stemming from disturbances to the hypothalamic–pituitary–adrenal axis. There is growing evidence to support the considerable impact of CRF on urinary bladder function. This neurohormone has been found to decrease the threshold of afferent impulsation of the micturition reflex and to increase bladder detrusor contraction activity. CRF also plays an important role in micturition control mechanisms at the level of the spinal cord [30]. Preclinical studies have shown that selective CRF₁ antagonists reduce DO symptoms [10]. It has been shown that selective destruction of afferent C-fibres leads to decreased expression of CRF, which indicates that this neurohormone is important for conducting the afferent impulsation from the urinary bladder [31]. Increased CRF expression has also been found in the urothelium and suburothelial ganglions in an animal model of cystitis.

It has been shown that brain regions characterized by a high density of CRF₁ receptors (such as the hippocampus, the prefrontal cortex and Barrington’s nucleus in the brainstem amygdala), apart from their well-known role in the body’s response to stress factors, are also involved in regulation of the micturition reflex, and this suggests that antagonists to this receptor might be an interesting target for OAB pharmacotherapy, especially in patients with accompanying depression [32]. Another CNS structure found to be a common element in the aetiopathogenesis of OAB and depression is the anterior cingulate cortex, whose increased activation has been detected on MRI in patients with OAB and patients with depression. SPECT also shows features of hypoperfusion and hypometabolism of this structure in both these groups of patients.