A randomized, double-blind, placebo-controlled study to assess efficacy of mirtazapine for the treatment of diarrhea predominant irritable bowel syndrome

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder with a relapsing/ remitting course. It is a symptom-based condition defined by abdominal pain and discomfort in association with altered bowel habits, with no identifiable cause [1]. It approximately affects 7–18% of the population worldwide and is more common in women than men [2]. IBS based on patients’ predominant stool pattern clinically is classified into four subtypes: with diarrhea (IBS-D), with constipation (IBS-C), mixed type (IBS-M), and un-subtyped (IBS-U). Determining the subtype of IBS is important for both diagnosis and treatment [3]. Although no decrease in life expectancy attributable to IBS has been observed, it generates a significant burden to both patients and society as a result of direct medical costs, lost productivity, and reduced health-related quality of life [4]. Management of IBS is based upon a multifactorial approach and includes non-pharmacological and pharmacological interventions [5]. Due to the high prevalence of psychiatric disorders in patients with IBS, anxiolytics and antidepressants agents, especially the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) commonly used for management of IBS symptoms. However, it is believed that the benefits of antidepressants in IBS treatment are not limited only to their anxiolytic and antidepressants effects. They may also have peripheral effects on pain perception, visceral hypersensitivity, and GI motility that could help patients with IBS-D [6]. However, although a number of pharmacological treatments are available for the treatment of IBS, most of the currently available drugs focus on alleviating symptoms rather than targeting the underlying pathophysiology. As a consequence, there is no satisfactory treatment at present for the management of IBS, and vast numbers of patients with IBS experience suboptimal clinical relief from current treatments [7]. Thus, there is a need for alternative effective pharmacological treatment for IBS.

For the development of new effective treatments for IBS, a better understanding of the potential underlying mechanisms involved in the generation of symptoms is crucial. Although, the exact pathophysiology of IBS has not yet been fully elucidated, overall, symptoms appear to be related to alterations in GI motility and/or enhanced visceral sensitivity [8]. Serotonin (5-HT) is an important neurotransmitter and paracrine signaling molecule in the gastrointestinal tract that it’s releasing from enterochromaffin (EC) cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes [9]. A large body of evidence indicates that abnormalities of serotonergic function have a central role in both intestinal and extraintestinal symptoms of IBS [10]. It has been found 5-HT dysfunction in the gut by affecting intestinal motor and secretory function may lead to either constipation or diarrhea. Additionally, altered 5-HT signaling in the central nervous system and the gut contributes to hypersensitivity in IBS [11]. These causative mechanisms suggest that therapies targeting altered serotonin signaling may provide new, effective treatments for patients with IBS. Several serotonin receptor subtypes have been identified that of which the most interesting targets for pharmacological intervention for IBS are 5-HT3 and 5-HT4 receptors subtypes [12].

Around one-third of patients with IBS meet the criteria for IBS-D with common symptoms of abdominal pain or discomfort, frequent loose stools, and urgency [13]. It is well known that 5-HT3 receptor antagonists by diminishing motor and secretory reflex activity and decreasing the activation of extrinsic sensory neurons that transmit signals to the brain can improve symptoms of stool frequency, urgency, abdominal discomfort, and stool consistency in patients with IBS-D [14]. In this view, a recent systematic review and meta-analysis of randomized controlled trials also reported that 5-HT₃ receptor antagonists are effective for treating non-constipated IBS and IBS-D. However, although rare, there are still clear concerns regarding the occurrence of serious adverse effects such as ischemic colitis with these agents [15]. Thus, the constant search is ongoing to identify new more effective, and better tolerated 5-HT3 receptor antagonists for the management of IBS-D. One strategy is the search on the existing drugs with known 5-HT3 receptor antagonist property that there is extensive clinical experience in their use and their safety profile.

Mirtazapine is an atypical antidepressant drug that exhibits both noradrenergic and serotonergic activity. Mirtazapine promotes the release of noradrenaline and serotonin by blocking α₂-adrenergic autoreceptors and α₂-adrenergic heteroreceptors, respectively. It also enhances serotonin neurotransmission, mainly through 5-HT_1A receptors by blocking postsynaptic 5-HT_2A, 5-HT_2C, and 5-HT₃ receptors [16]. Since introduction, because of its unique mechanisms of actions, in addition to treating depression and anxiety, the potential usefulness of mirtazapine in the treatment of many other psychiatric and medical conditions has been investigated [17]. Considering the 5-HT3 receptor antagonist property of mirtazapine, it may be also a valuable therapeutic option for the management of patients with IBS-D and preliminary evidence indicates its beneficial effects [18, 19].

However, there are only case reports and open-label studies, and double-blind, placebo-controlled studies with mirtazapine in the treatment of IBS-D are lacking. Hence, we designed this double-blind, placebo-controlled study to evaluate whether compared to placebo, mirtazapine would be efficacious and safe in the treatment of patients suffering from IBS-D.

Based on our best knowledge, our study for the first time in a randomized, double-blind, and placebo-controlled study evaluated the influence of mirtazapine on clinical outcomes of patients with diarrhea-predominant IBS. This study showed that in comparison to the placebo, mirtazapine was more effective in decreasing the severity of IBS symptoms (based on the IBS-SSS questionnaire). Further, compared to placebo, mirtazapine increased stool consistency, decreased stool frequency, decreased urgency and abdominal pain scores, and increased the rate of days without bowel urgency, pain, and diarrhea. Additionally, while was acceptably well-tolerated, treatment with mirtazapine improved the patients’ quality of life as well as psychological symptoms such as anxiety.

Diarrhea-predominant IBS is a debilitating form of IBS which significantly reduces the quality of life of patients, increases health care expenditures, impairs social and occupational functioning, and increases psychological disorders [28]. Despite its high burden, the choice of treatments of IBS-D by patients or their practitioners is still challenging. Although a number of different pharmacological treatments are available for the management of patients with IBS-D, no treatment has been shown to have sufficient efficacy and safety and most of the patients continue to suffer from symptoms [29]. The pathophysiology of IBS is not precisely understood yet and likely it has multifactorial etiopathogenesis. From the biological point of view, the coordination between the central nervous system and gastrointestinal contractility is regulated through a variety of brain-gut peptides and gastrointestinal hormones [30]. Among a variety of neurotransmitters that can evoke IBS symptoms, serotonin has key contributory roles in its pathogenesis. Serotonin is an important signaling molecule in the activation of motor and secretory reflexes, and in the activation of sensory signals in the brain-gut axis. It is becoming increasingly clear that dysfunctions of the central or peripheral serotonergic system can be involved in the pathophysiology of IBS [15]. In this context, it has been reported that patients with IBS-D might have reduced serotonin reuptake, and those with IBS-C might have impaired release of serotonin [31]. Further studies have also indicated that post-infective IBS is associated with increased serotonin containing enteroendocrine cells [32] and increased postprandial serotonin release [33]. There is also evidence of an association between serotonin transporter gene polymorphism and the diarrhea-dominant IBS phenotype. Indeed, it seems that the reduction of serotonin transporter expression could result in raised serotonin levels and contribute to symptoms in patients with IBS-D [34]. Among multiple subtypes of the receptor for serotonin, it is well recognized that the 5HT3 subtype plays an important role in gut function. It has been also known that signaling from the gut to the central nervous system is predominantly 5-HT3 mediated [35]. Further, it is well-known that in diarrhea-predominant IBS, activation of serotonin receptors belonging to the 5-HT3 subtype by increasing the firing rate of secretomotor neurons increase intestinal motility and secretion [36]. In line with this evidence, it is found that 5-HT3-receptor antagonists retard colonic transit, reduce secretion, reduce visceral sensitivity via both peripheral and central nervous receptors system mechanisms, and increase colonic compliance in response to distension [37]. Actually, it is found that the 5-HT3 receptor antagonists by inhibiting 5-HT₃ receptors located on intrinsic sensory neurons can diminish motor and secretory reflex activity, and by decreasing the activation of extrinsic sensory neurons and vagal afferents, which are involved in the transmission of noxious and non-noxious (eg, nausea, bloating) sensations respectively, decrease the visceral pain and discomfort associated with IBS [38]. So, this evidence makes 5-HT3 antagonists as a logical treatment in the management of patients with IBS-D. In line with this, a recent systematic review and meta-analysis by Zheng et al. showed that 5-HT₃ receptor antagonists relieve global IBS-D symptoms, abdominal pain and discomfort, urgency, stool consistency, and stool frequency in non-constipated IBS and IBS-D [15]. However, despite the substantial evidence of their effectiveness, due to concern regarding occurrence rare but serious adverse events such as severe constipation and ischemic colitis, place of 5-HT₃ receptor antagonists such as cilansetron and alosetron in the treatment of IBS-D being restricted to patients with severe refractory IBS-D who have failed to respond to the usual conventional treatment [35]. Therefore, there is a need for alternative safe and efficacious pharmacological treatment for IBS-D. It seems that instead of new drug discovery, attempts to introduce agents with 5-HT3 receptor antagonist property from already-existing drugs with known adverse drug reaction profiles may be a good strategy.

One of these agents is mirtazapine. Mirtazapine is an antidepressant and antianxiety agent that because of the unique mechanism of action, since introduction, its use in a wide range of conditions has been investigated [16]. Recently, some clinical studies also have addressed its effectiveness in the management of functional gastrointestinal symptoms. In this regard, Jiang et al. in their recent study in functional dyspepsia patients with weight loss reported that mirtazapine not only alleviates symptoms associated with dyspepsia and depression but also significantly increases body weight. They also observed that the clinical efficacy of mirtazapine may be mediated in part through the regulation of brain-gut or gastrointestinal hormones [39]. Similar to these findings, results of another study by Tack et al. also showed that compared to placebo mirtazapine at a dose of 15 mg/day can improve early satiation scores and nutrient tolerance in functional dyspepsia patients with weight loss [40]. Recently by Sanagapalli and colleagues in an open-label study, the efficacy of mirtazapine in the treatment of IBS-D was also investigated. Consistent with our findings, in this study mirtazapine demonstrated considerable beneficial effects on both gastrointestinal and psychological symptoms in patients with IBS-D [18]. Also, in one case report, mirtazapine was an effective agent in the improvement of debilitating IBS symptoms in a woman that mirtazapine was initiated by her psychiatrist for treatment of comorbid depression [19]. Spiegel et al. also reported mirtazapine was effective in improving both psychopathological symptoms and diarrhea and constipation symptoms in a 66-year-old woman suffering from a 1-year history of IBS-mixed type [41].

Although the beneficial effects of mirtazapine in the treatment of IBS-D mainly stem from its strong antagonistic activity against central and peripheral 5HT3 receptors [42], it seems that mirtazapine has a number of other possible mechanisms of action in the treatment of IBS-D. There is a large body of evidence suggesting that mast cell activation which contains granules rich in mediators such as histamine plays an important role in the development of major IBS symptoms, such as abdominal pain, constipation, and diarrhea [43]. High levels of histamine were found from supernatants from IBS colonic samples [44]. Moreover, it has been observed that the expression of histamine1 (H1) and H2 receptors in the intestinal tissue samples of IBS patients is up-regulated [45]. It is found that histamine by activation enteric neurons through H1 and H2 receptors contributes to visceral hypersensitivity [46]. This causative mechanism suggests the possible application of anti-histamine agents as a potential therapeutic option in the management of IBS and interestingly enough, some experimental and clinical studies have provided promising evidence regarding the effectiveness of these agents in the treatment of IBS [47‐49]. Mirtazapine is also found to have a high affinity for central and peripheral H1receptors and acts as a potent antagonist of H1 receptors [50]. So, it seems that the anti-histamine property of mirtazapine may be another potential mechanism of its action for treating IBS.

Recently accumulated experimental and clinical evidence has reported that mirtazapine like TCAs, as a dual-acting antidepressant, has also marked antinociceptive effects that offer this possibility that mirtazapine used in the management of various chronic pain conditions [51‐54]. As regards the mechanism of action, it is believed the antinociceptive effect of mirtazapine unrelated to its antidepressant and antianxiety effects. It seems mirtazapine mainly via modulation of serotonin and noradrenaline pathways in the brain, and selective interaction with multiple 5-HT receptors exerts its antinociceptive effects [54, 55]. Beyond this, in recent years mounting of evidence has pointed out that Kappa opioid receptors which are located on the terminals of a variety of neurons, including those extrinsic visceral afferent neurons exhibit visceral analgesic and antihyperalgesic activity [56, 57]. Preliminary evidence suggests that beside serotonergic and noradrenergic receptors, the antinociceptive effects of mirtazapine is partially mediated by the opioidergic system, particularly through activation of the kappa3-opioid receptor subtype [54, 55].

It is well-known that psychological stress playing a major role in the onset and exacerbation of IBS symptoms such as abdominal pain and altered bowel movements [58]. Considering that psychiatric comorbidities such as anxiety and depression are highly prevalent in IBS patients [59], and psychopharmacological agents commonly employed by clinicians as an alternative therapy for the management of IBS symptoms, especially IBS-D [6], it seems that the anxiolytic and antidepressant effect of mirtazapine is an additional mechanism that may indirectly through it alleviate IBS symptoms.

Taken together, considering the above-discussed mirtazapine ways of action, it can exert beneficial effects on IBS symptoms via multiple potential mechanisms of action. Interestingly enough benefits of mirtazapine treatment in patients with IBS-D are amplified by the fact that it is effective as both an etiological and symptomatic treatment in these patients. Further, the attractiveness of mirtazapine for the treatment of IBS also stems from its good tolerability and safety profile. Dry mouth, sedation, and weight gain are the most common side effects of mirtazapine that tolerance to side effects such as sedation can develop with ongoing therapy [16]. Further, its appetite stimulation may be welcome in patients with anorexia and low BMI [39, 40]. Evidence concerning the effect of mirtazapine on muscarinic-cholinergic receptors is limited. Although previously, some experimental evidence indicated that mirtazapine has a low affinity for central and peripheral muscarinic-cholinergic receptors [60, 61], recently preliminary evidence suggests that mirtazapine interacts with muscle and neuronal muscarinic and nicotinic receptors as well [62, 63]. However, the clinical importance of the anticholinergic effect of mirtazapine especially in a matter of its tolerability remains unclear. However, it is obviously clear that Mirtazapine particularly in the case of anticholinergic side effects generally better tolerated than the traditional TCAs that are routinely used in the management of IBS symptoms [64]. Therefore, this margin of safety and excellent efficacy makes mirtazapine as a promising agent for the management of IBS-D.

Despite the novelty, the findings of our work should be interpreted within its limitations. The first limitation of this study is the relatively small number of subjects and the relatively short duration of the follow up that can affect the generalization of our results. More studies with larger sample sizes and longer follow-up visits are warranted to validate the findings reported here. The second limitation of the study is that the patients in our study received a relatively modest dose of mirtazapine; maybe higher doses show better effects on the improvement of symptoms or different tolerability. Third, for the assessment of the rate of occurrence of adverse effects, we relied on the patients’ self-reporting. Since patients may not recognize all drug-related side effects, thus the actual incidence of side effects may be underestimated in this study. Hence, using a standard instrument to identify adverse effects in advance in future studies can estimate more precisely the incidence of adverse effects. Last but not least, we investigate the effectiveness of mirtazapine in patients with diarrhea-dominant IBS. Additional trials are needed to evaluate the effectiveness of mirtazapine for the treatment of other types of IBS.

In conclusion, compared to placebo, mirtazapine not only alleviated gastrointestinal symptoms of patients with IBS-D but also improved QOL as well as psychological symptoms such as anxiety of these patients. Despite the limitations of our study that make a drawing strong conclusion difficult, our study provides primary evidence that patients suffering from IBS-D symptoms, particularly those with concomitant psychological symptoms, by the administration of mirtazapine experience significant improvement in gastrointestinal symptoms of IBS-D but also in psychological aspects and QOL, as do traditional TCAs. Given that mirtazapine is generally better tolerated than TCAs, this evidence makes mirtazapine an attractive therapeutic option in the treatment of IBS. However, future studies with larger sample size and longer follow-up periods would be necessary to clarify the optimal dose as well as the safety and efficacy of mirtazapine in patients with other subtypes of IBS.