The 5-HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week, open-label trial

Systemic sclerosis (SSc) is a chronic autoimmune fibrotic disease affecting the skin and other organs including the gastrointestinal tract. The esophagus is commonly affected in SSc and esophageal function is compromised in up to 90 % of patients [1, 2]. Symptoms of esophageal disease are due to gastroesophageal reflux disease (GERD) and esophageal motor dysfunction. Thus, heartburn, regurgitation and dysphagia have been reported by 80 % of patients with SSc [3, 4].

Although several medications are used in patients with symptomatic SSc and esophageal involvement, there is no universally effective treatment. The current therapeutic approach includes administration of proton pump inhibitors (PPIs) and prokinetics agents (including metoclopromide, erythromycin, cisapride and domperidone), although the evidence to support their use is limited [5]. It is well-known that there are many issues in the efficacy and long-term use of the currently available prokinetic drugs; use of metoclopromide or erythromycin or cisapride is restricted due to safety profile issues and administration route problems, while administration of domperidone has no effect on esophageal motor dysfunction in patients with symptomatic SSc [6].

Animal studies have identified serotonin (5-hydroxytryptamine, 5-HT) as one of the putative neurotransmitters involved in esophageal motor function making its receptors suitable therapeutic targets [7]. Studies in healthy volunteers show that acute administration of buspirone, a 5-HT₁A receptor agonist, has a strong stimulatory effect on esophageal peristalsis and lower esophageal sphincter (LES) function [8, 9]. Moreover, we have recently observed that acute administration of buspirone exerts a beneficial effect on esophageal motor dysfunction associated with SSc [6]. Thus, in order to investigate whether buspirone exerts a long-term effect in SSc-associated esophageal involvement we conducted a prospective 4-week open-label trial. The primary objective was to assess the efficacy of buspirone on LES dysfunction. The secondary efficacy endpoint was change in esophageal symptoms after buspirone administration.

Heartburn and regurgitation were reported by almost all patients (91 % and 86 %, respectively), while dysphagia was reported by 54.5 % of patients. Only 36 % of patients reported chest pain as one of their symptoms. Moreover, regurgitation and heartburn were the most bothersome symptoms reported to a similar extent, followed by dysphagia and chest pain (Table 1).

Effect of buspirone on manometric parameters

Following buspirone administration for 4 weeks the LES resting pressure significantly increased from 7.7 ± 3.9 to 12.2 ± 4.6 mmHg (p < 0.00005). Figure 1 increased LES resting pressure after buspirone administration was observed in 15 patients (68 %) with a range of 4–13 mmHg (41–220 %, accordingly). There were significantly fewer patients with hypotensive LES after compared to before buspirone administration (8/22 vs. 17/22, respectively, p = 0.006).

In contrast to LES resting pressure, buspirone administration had no effect on LES residual pressure or on IRP (Table 2). In addition, buspirone administration did not increase the duration and velocity of esophageal body contractions or the amplitude of contractions, compared to baseline values (Table 2). Buspirone was well-tolerated by all patients who completed the study.

	Baseline	After buspirone	p
Amplitude (mmHg)	16.6 ± 9.6	17.5 ± 9.6	0.163
Velocity (cm/sec)	3.7 ± 2.4	3.4 ± 1.9	0.701
Duration (sec)	2.6 ± 1.9	3.1 ± 2.3	0.668
LES resting pressure (mmHg)	7.7 ± 3.9	12.2 ± 4.6	0.00002
LES residual pressure (mmHg)	2.9 ± 1.9	3.2 ± 2.1	0.157
IRP (mmHg)	3.1 ± 2.3	3.5 ± 2.1	0.143

LES lower esophageal sphincter, IRP integrated relaxation pressure

Treatment of patients with symptomatic SSc and esophageal involvement is still an area of unmet need, as there is no available treatment with established efficacy. Administration of PPIs and prokinetic drugs do not appear to provide substantial symptomatic relief in patients with SSc and esophageal symptoms [5]. Pathophysiology of gastrointestinal dysmotility in SSc is multifactorial and different neurotransmitters could be involved in this process [15, 16]. Serotonin (5-HT) is considered a key neurotransmitter and acute studies, both in healthy subjects and patients with SSc, have shown that agonists of specific class of its receptors, such as 5-HT₁A, could be a putative therapeutic option [6, 8, 9]. Buspirone had been initially developed for clinical use in the treatment of depression and anxiety disorders. Its mechanisms of action are thought to include agonistic actions, mainly on 5-HT₁A receptors, but also on dopamine D2 receptors. Buspirone is absorbed rapidly and almost completely with a t_max = 0.89 ± 0.15 h [17].

To the best of our knowledge no previous study has prospectively investigated whether a pharmaceutical agent may help patients with SSc and esophageal involvement. The results of our open-label, prospective 4-week trial suggest that the 5-HT₁A receptor agonist, buspirone, given orally for 4 weeks, significantly increases the LES resting pressure by 41 % to 220 % over the baseline values in almost 70 % of patients with SSc. Furthermore, patients with a less dilated esophagus as detected on chest CT had a better response to buspirone administration. This is an important aspect of our study, as patients with SSc undergo routine chest CT as a screening test for lung fibrosis. Many studies have suggested that measurement of esophageal coronal diameter on chest CT is a marker of the functional status of the esophagus in SSc and a dilated esophagus represents more severe visceral involvement [18, 19].

Herein, the 4-week administration of buspirone also alleviated heartburn and regurgitation in the majority of patients. Buspirone seems more effective for GERD-related symptoms, whereas symptoms related to esophageal hypomotility, such as dysphagia and chest pain are not affected. Thus, we could suggest that buspirone administration may be most helpful for the subgroup of SSc patients with reflux symptoms. An objective assessment of reflux response with pH-impedance measurement could certainly enhance our results.

As all patients were on PPIs before and during the study period, the strategy with add-on buspirone could be a worthwhile therapeutic option. Keeping in mind the anecdotal evidence that persistent reflux contributes significantly to the development of interstitial lung disease and/or progress, which is the leading cause of death in SSc, the potential beneficial effect of buspirone becomes more important. Buspirone-associated improvement in the severity of reflux symptoms can be explained by a strong stimulatory effect on LES resting pressure. However, other mechanisms cannot be excluded. Comorbid psychiatric diseases in patients with a chronic disorder, such as SSc, and especially anxiety, are common [20, 21]. Buspirone is used as anxiolytic drug in clinical practice. Therefore, a potential alteration in the sensitivity by decreasing the anxiety level may play a role in symptom improvement. As we did not include measurement of anxiety scores, this is a limitation of the present study. However, in the event that the main mechanism underlying symptom improvement with buspirone was the anxiolytic effect of the drug, other non-reflux symptoms should have been improved.

A limitation of the present study, due to restrictive regulatory rules that we were unable to overcome, is that it is not a randomized, placebo-controlled investigation and there is a lack of a control arm. Another limitation is the relatively small number of patients studied; however, we have to keep in mind that patients with SSc due to the chronic nature of their disease have several medical disabilities, making recruitment very challenging. The use of a validated questionnaire, such as the UCLA STCC SSc-GI [22] rather than a self-reported one could strengthen our results, however, this questionnaire, which covers a broad spectrum of gastrointestinal symptoms in patients with SSc, is not validated in Greek. Moreover, the majority of available questionnaires are focused on reflux symptoms rather than on dysmotility-associated symptoms characterizing SSc.

Buspirone was well-tolerated in the present study. Treatment interruption due to adverse effects (dizziness and nausea) was observed in only 4 out of 30 patients. Patients who completed the study reported sporadic and self-limited adverse effects that did not affect their daily activities.

In conclusion, our study showed that 4-week daily administration of buspirone increases the LES resting pressure and improves esophageal symptoms in the majority of SSc patients with esophageal involvement. Furthermore, buspirone exerts a greater beneficial effect on patients with less severely affected esophageal function as detected on chest CT, suggesting a therapeutic role mainly in patients with earlier or less severe involvement. Although further evaluation in placebo-controlled studies is warranted, buspirone could potentially be given under observation for objective improvement in all patients with SSc who report reflux symptoms, despite undergoing standard treatment.