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Abstract

Background:

Functional dyspepsia (FD) is one of the most common gastrointestinal disorders worldwide. Currently, anti-gastric drugs, gastric acid inhibitors, prokinetic drugs, and mucosal protective drugs are widely used in FD patients, however, only a small proportion of patients benefit from these drugs. Studies reported mirtazapine may improve symptoms of FD patients but the efficacy and safety of mirtazapine in the treatment of FD is unclear.

Objectives:

To investigate the efficacy and safety of mirtazapine in FD patients.

Design:

We performed a prospective, single-randomized, two-group parallel clinical trial involving 120 FD patients with poor traditional drug treatment outcomes to evaluate the efficacy and safety of mirtazapine.

Methods:

Qualified patients identified through the screening assessments were randomly divided into two groups: mirtazapine group (n = 60) treated with mirtazapine 15 mg qn on top of traditional drugs, and control group (n = 60) who continued to be treated with traditional drugs. Subjects were evaluated for meal-related symptoms and severity, quality of life, gastrointestinal-specific anxiety, and body weight before and after the 8-week intervention. Adverse reactions were also recorded.

Results:

At the end of 8-week treatment, dyspeptic symptoms in the mirtazapine group were significantly relieved compared with the baseline (7.95 ± 1.86 vs 11.17 ± 2.14, p < 0.001). Assessment of the impact of dyspepsia on patients’ quality of life from the short form-Nepean Dyspepsia Index showed that patients generally feel better in mirtazapine group than control group (24.52 ± 2.87 vs 28.64 ± 4.32, p < 0.001). Mirtazapine group also showed significant weight gain and decreased visceral sensitivity index score.

Conclusion:

Compared with control group, 8-week administration of mirtazapine significantly improved the overall severity of symptoms of dyspepsia (such as individual symptoms of postprandial fullness, early satiation, nausea, and vomiting), gastrointestinal-specific anxiety, quality of life, and increased weight in FD patients. This study provided clues to clinicians that mirtazapine may be a good choice for the treatment of FD patients.

Trial registration:

This study was registered in the Chinese clinical trial registry (https://www.chictr.org.cn/index.html, protocol No. ChiCTR2100048304).

Plain language summary

The efficacy and safety of mirtazapine in functional dyspepsia (FD) patients

Functional dyspepsia (FD) is one of the common gastrointestinal disorders worldwide. Currently anti gastric drugs, gastric acid inhibitors, prokinetic drugs, mucosal protective drugs are widely used in FD patients, however, only a small proportion of patients benefits from these drugs. Studies reported mirtazapine may improve symptoms of FD patients but the efficacy and safety of mirtazapine in the treatment of FD is unclear. To investigate the efficacy and safety of mirtazapine in functional dyspepsia (FD) patients. We performed a prospective clinical trial involved 120 FD patients with poor traditional drugs treatment outcomes to evaluate efficacy and safety of mirtazapine. Qualified patients identified through the screening assessments were randomly divided into mirtazapine group and control group. Subjects were evaluated for meal-related symptoms and severity, quality of life, gastrointestinal-specific anxiety and body weight before and after the 8-week intervention. Compared with control group, 8-week administration of mirtazapine significantly improved the overall severity of symptoms of dyspepsia (like individual symptoms of postprandial fullness, early satiation, nausea and vomiting), gastrointestinal-specific anxiety, quality of life and increased weight in FD patients. This study provided clues to clinicians that mirtazapine may be a good choice for the treatment of FD patients.

Keywords

functional dyspepsia (FD)drug therapy mirtazapine

Introduction

Functional dyspepsia (FD) is one of the common gastrointestinal disorders with a global prevalence of 10%–30%.¹ The overall prevalence of dyspepsia among urban residents in Guangdong, China is 18%. It is more common in the older age groups, reaching 27% in the group from 50 to 59 years old. Patients with dyspepsia as the main complaint account for more than 50% of cases in gastroenterology clinics.² In the UK, it is estimated that £450 million is spent on dyspeptic drugs each year.³

FD patients with weight loss may experience more frequent clinical visits, higher psychological disorders, poorer appetite, and lower quality of life.⁴ The pathogenesis of the disease has not yet been fully understood. Currently, in clinical practice, anti-gastric drugs, gastric acid inhibitors, prokinetic drugs, and mucosal protective drugs are widely used in FD patients. However, reports showed that these drugs only improve symptoms in a small proportion of patients, while the majority of patients do not benefit significantly from these drugs.³

From a pharmacological perspective, mirtazapine has antagonistic effects on histamine receptors H1, α2 adrenergic receptors, 5-HT2C, and 5-HT3 receptors, and it has been reported in publications to improve dyspeptic symptoms, inhibits nausea and vomiting, and has good therapeutic effects in FD.⁵ However, based on the manufacturer’s instructions, the use of mirtazapine is limited to the treatment of depression and anxiety disorders. Few evidence exists to support or contradict these claims for FD patients.

The aim of this trial was to observe the efficacy and safety of mirtazapine in the treatment of FD. The choice between mirtazapine and other common drugs in clinical digestive dynamics often comes down to the clinicians’ personal preference and experience.

Materials and methods

Study design

This was a two-group parallel, single-blinded, single-site randomized clinical trial in the Department of Gastroenterology, Zibo Central Hospital, China. The trial included an 8-week intervention. A 1:1 single-blinding randomization plan was performed using sealed envelopes. Patients were blinded to study assignment through the period of randomized follow-up. Data were collected at enrollment, 8-week, and unscheduled follow-up visits. Physicians responsible for follow-up were unblinded throughout the trial.

Reporting follows the CONSORT guidelines.⁶

Diagnostic criteria for FD

According to the Rome IV, diagnostic criteria for FD as: (1) meeting one or more of the following criteria: (a) postprandial discomfort; (b) early satiety; (c) epigastric pain; (d) burning sensation in the epigastrium; (2) no evidence of structural disease (including gastroscopy) that could explain the above symptoms (symptoms present for at least 6 months prior to diagnosis and meeting the above diagnostic criteria for the last 3 months). Based on their symptom profile, FDs are divided into two subtypes: postprandial discomfort syndrome (PDS) and epigastric pain syndrome.⁷

Patient selection

Patients (18–70 years old) from June 2021 to December 2021 who met the diagnostic criteria for FD of Rome IV were selected. Before entering the clinical trial, these patients were treated with proton pump inhibitors, digestive enzymes, and motivational drugs for 2 weeks, and their total dyspeptic symptom score dropped by less than 30%.

Exclusion criteria: (1) Patients had a known mirtazapine allergy; (2) Other mental illnesses, serious physical diseases; (3) Participants in other clinical trials within the past 3 months; (4) Women during pregnancy or breastfeeding; (5) Patients considered unsuitable to be to participate in this study by the investigator.

Totally 120 eligible participants were randomly allocated to two supervised groups: (1) mirtazapine group, a group that was treated with traditional drugs (combizym + domperidone) along with mirtazapine 15 mg qn, (2) control group, a group that continued with traditional drugs (combizym + domperidone) (Figure 1). Specifically, each tablet of combizym contains 24 mg of Aspergillus oryzae extract (cellulase 70 FIP U, protease 10 FIP U, amylase 170 FIP U) and 220 mg of pancreatic enzyme (lipase 7400 Ph.Eur.U, protease 420 Ph.Eur.U, and amylase 7000 Ph.Eur.U). Each patient in the control group took combizym one tablet tid and domperidone 10 mg tid.

Figure 1.

Trial flow diagram.

Before enrollment, all participants must provide written informed consent that has already been approved by the Institutional Review Board (IRB) of Zibo Central Hospital (approval number: 202105001).

After admission, patients underwent routine physical examination (including weight and blood pressure) laboratory tests, including routine blood tests, urine tests, stool tests and occult blood, liver function, kidney function, abdominal ultrasound or CT, and gastroscopy. These above indicators were reassessed after 8 weeks. Patients who have already undergone these tests within 1 month before admission would not be examined again.

Symptom assessment

The severity of dyspeptic symptoms was assessed according to the dyspepsia symptom severity (DSS) questionnaire for FD patients in the last week, consisting of eight dyspeptic symptoms (postprandial fullness, upper abdominal bloating, early satiation, nausea, belching, epigastric pain, vomiting, and epigastric burning).⁸ The scales were listed as: 0—no symptoms, 1—symptoms noted when prompted, 2—self-conscious symptoms that do not affect work and life, and 3—significant symptoms that affect work and life. The total score of the above symptoms was the DSS score. All patients were assessed with the short form-Nepean Dyspepsia Index (SF-DNI) which reflects the impact of dyspepsia on patients’ quality of life and the visceral sensitivity index (VSI) which reflects gastrointestinal-specific anxiety.^9,10 Meanwhile, participants were instructed to report any adverse events during the 8-week intervention period.

Statistical analysis

The sample size calculation was conducted using PASS Statistical Software (2021) (NCSS, LLC.; ncss.com/software/ncss). Based on our pilot data and the available literature, we estimated a 10% decrease in DSS scores in mirtazapine groups than the control group with an expected standard deviation of 1.5. A sample size of 98 patients (49 control and 49 intervention) would have a power of 90% with an α of 0.05 to detect this difference. Considering a 15% dropout, this study needed at least 58 participants in each group.

Continuous variables are expressed as the mean ± standard deviation or the median (inter-quartile range). Categorical variables are sorted as frequencies (percentages). The outcomes were compared between baseline and week 8 within each treatment (the mirtazapine group and the control group) separately by paired or Student t-tests. Then for each outcome, the changes between baseline and week 8 were compared across treatment groups using two sample t-tests.

All analyses were performed using software Stata 16.0 (Stata Corporation, College Station, TX, USA) and GraphPad Prism 9 (GraphPad Prism Software Inc., San Diego, CA, USA). A two-sided p < 0.05 was regarded as statistically significant.

Results

Clinical data

One hundred and twenty patients were assessed for eligibility and finally were in this trial and randomly allocated to two supervised groups: mirtazapine group and control group. Two patients in the mirtazapine group withdrew from the trial due to drowsiness and sleepiness. One patient in the control group withdrew due to pruritus. The difference in gender and age between the two groups was not statistically significant (p = 0.19, 0.88, respectively; Table 1).

Table 1.

Comparison of baseline characteristics of patients in two groups.

Group	Mirtazapine (n = 58)	Control (n = 59)	P
Age (‾x ± s)	43.93 ± 13.27	43.58 ± 11.86	0.88
Sex			0.19
Male	29 (50.0%)	37 (62.71%)
Female	29 (50.0%)	22 (37.29%)

Symptom outcomes

At the end of 8-week treatment, dyspeptic symptoms in the mirtazapine group were significantly relieved compared with the control group (11.17 ± 2.14 vs 7.95 ± 1.86, p < 0.001) (Table 2). Among the eight dyspeptic symptoms from DSS, postprandial fullness (2.45 ± 0.50 vs 0.97 ± 0.67, p < 0.001), early satiation (1.65 ± 0.58 vs 0.84 ± 0.59, p < 0.001), nausea (1.35 ± 0.74 vs 0.74 ± 0.08, p < 0.001) and vomiting (0.97 ± 0.09 vs 0.45 ± 0.06, p < 0.001) were reported to have significantly improved in the mirtazapine group at the end of 8-week treatment (Figure 2, Table S1).

Table 2.

Differences between groups at the end of 8-week treatment.

Group	DSS	NDI	VSI	Weight
Baseline
Mirtazapine	11.50 ± 1.81	28.47 ± 3.90	32.55 ± 2.68	62.39 ± 5.40
Control	11.31 ± 1.98	29.22 ± 4.21	32.32 ± 2.29	59.54 ± 4.82
8-week intervention
Mirtazapine	7.95 ± 1.86	24.52 ± 2.87	25.53 ± 1.94	66.57 ± 5.18
Control	11.17 ± 2.14	28.64 ± 4.32	31.81 ± 2.08	60.49 ± 4.20
P1	0.5791	0.3172	0.6189	0.0030*
P2	<0.001*	<0.001*	<0.001*	<0.001*

P1: Baseline comparison between mirtazapine group and the control group.

P2: Comparison across groups (post-pre mirtazapine) versus (post-pre control).

p < 0.05.

DSS, dyspepsia symptom severity; SF-DNI: Short Form-Nepean Dyspepsia Index; VSI: Visceral Sensitivity Index.

Figure 2.

Changes in DSS score after 8-week of mirtazapine (a) or control (b) group.

Results showed that mirtazapine was superior to the control group in reducing the SF-NDI score after 8-week treatment (24.52 ± 2.87 vs 28.64 ± 4.30, p < 0.001). Specifically, for the mirtazapine group, tension was relieved, interference with daily activities was increased and diet was balanced (Table 3). Also, we compared the scores of pre- and post-treatment item by item in the control group, there were no statistical differences (p > 0.05) (Table 3).

Table 3.

Comparison of the short form-Nepean Dyspepsia Index subscales within each group at the end of 8-week treatment.

Subscale	Baseline mirtazapine	8-week mirtazapine	Baseline control	8-week Control	P1	P2
Tension	6.16 ± 1.52	5.22 ± 1.70	5.64 ± 1.68	5.59 ± 1.66	<0.001**	0.833
Interference withdaily activities	5.88 ± 1.58	5.21 ± 1.54	6.07 ± 1.83	5.71 ± 1.95	0.041*	0.215
Eating/drinking	6.02 ± 1.78	4.26 ± 1.12	5.75 ± 1.57	5.58 ± 1.23	<0.001**	0.389
Knowledge/control	4.87 ± 1.66	4.62 ± 1.10	5.83 ± 1.76	6.24 ± 1.84	0.480	0.183
Work/study	5.60 ± 1.77	5.21 ± 1.91	5.93 ± 1.65	5.52 ± 1.76	0.282	0.130

P1: Comparison between baseline and 8-week treatment of mirtazapine group.

P2: Comparison between baseline and 8-week treatment of control group.

p < 0.05. **p < 0.001.

At the end of 8-week treatment, the mirtazapine group showed significant weight gain compared with the control group (66.57 ± 5.18 vs 60.49 ± 4.20, p < 0.001). When comparing the changes in VSI scores, FD patients accepting mirtazapine reported a more decrease than the control group (25.53 ± 1.94 vs 31.81 ± 2.08, p < 0.001) (Table 2).

Adverse effects

In the mirtazapine group, one patient experienced dizziness, eight patients experienced drowsiness and sleepiness, one patient experienced fatigue, and two patients withdrew from the study due to drowsiness and sleepiness. In the control group, two patients experienced fatigue and one patient withdrew from the study due to pruritus.

Discussion

Dyspepsia is a common clinical condition and it is estimated that over 50% of people will seek medical attention for dyspepsia symptoms.¹¹ Most dyspepsia symptoms are prolonged and recurrent.¹² Some patients with dyspepsia may experience weight loss. Dyspepsia affects the patient’s work and daily life and patients consume a lot of medical resources.¹³ However, commonly used medications such as gastric acid inhibitors and prokinetic drugs do not provide significant benefit to the majority of FD patients.³ This prospective, randomized clinical trial with two parallel arms evaluated the safety and efficacy of mirtazapine in the treatment of FD patients.

The pathogenesis of FD involves many aspects. Proximal gastric relaxation provides a container for food, which increases the volume of the stomach without increasing the pressure in the stomach.¹⁴ Some patients with FD have impaired fundic adaptability, hyper-sensitivity, and impaired emptying.^5,15 Restoring impaired gastric tolerance is an effective target for improving early satiety and regaining weight.^14,16 The satiety test can be used as an alternative method of measuring stomach tolerance and as a non-invasive test.¹⁷ The results of our study showed that mirtazapine improved early satiety and postprandial fullness in FD patients, but had no effect on epigastric pain or epigastric burning. This study suggests that mirtazapine is more appropriate for patients with PDS, and mirtazapine is associated with peripheral mechanisms of action such as increased gastric tolerance and increased nutritional tolerance, as well as central mechanisms of action. These findings have also been found in other studies.^5,18,19

Weight loss is often considered to be an alarming symptom, but in fact, it is also frequently seen in FD patients. Patients with weight loss tend to have more frequent visits to the doctor, a higher incidence of psychological disorders, and a lower quality of life. So the burden of disease is therefore particularly higher for them.²⁰ Impaired gastric tolerance in patients with FD is associated with early satiety and weight loss.²¹ After 8 weeks of mirtazapine, the patients had a significant weight gain, which suggested that mirtazapine was more suitable for FD patients with weight loss.

A study showed that serum growth hormone-releasing peptide, neuropeptide Y, gastric actin, and gastrin levels were significantly increased, while leptin, 5-hydroxytryptamine, and cholecystokinin levels were significantly decreased in patients after 8 weeks of mirtazapine administration.⁴ Previous evidence demonstrated that the effects of mirtazapine in improving dyspeptic symptoms and increasing body weight may be related to its modulation of the brain-gut axis and gastrointestinal hormones.⁴ In addition, mirtazapine may increase body weight by improving nutritional tolerance through a central mechanism.²²

More and more antidepressants are being used in patients with functional gastrointestinal disorders, and possible mechanisms include: (1) anxiety and depression exacerbate dyspeptic symptoms. Antidepressants may reduce the severity of psychological symptoms, particularly anxiety and depression, thereby improving dyspeptic symptoms; (2) antidepressants have a central analgesic effect and can reduce emotional arousal and restore sleep; (3) antidepressants may have local pharmacological effects on the upper gastrointestinal tract.²³ The VSI that reflects gastrointestinal-specific anxiety is negatively correlated with duodenal mucosal integrity. Impaired duodenal barrier function is involved in the pathogenesis of FD. Restoring the integrity of the duodenal barrier is a potential therapeutic target for FD.²⁴ Our study confirmed that mirtazapine improved gastrointestinal-specific anxiety scores, the short form-Nepean Dyspepsia Index scores, and digestive symptoms in FD patients. A study also suggested that mirtazapine improves gastrointestinal-specific anxiety by improving duodenal mucosal integrity and reducing duodenal inflammation.⁹

Mirtazapine is effective in improving nausea and vomiting in FD patients, which is related to its antagonism of 5-HT3 receptors.²⁵ In addition, mirtazapine is effective in early satiety and nausea in diabetic patients and can be used to treat refractory diabetic gastroparesis.²⁶ Our study showed that nausea and vomiting in the mirtazapine group were significantly relieved. Previous studies have indicated that mirtazapine could be a new approach to the clinical management of diabetic gastroparesis.^27,28 Mirtazapine is a tetracyclic antidepressant with a unique mechanism of action that exerts its antidepressant effects mainly through selective blockade of presynaptic α2 adrenergic receptors and selective blockade of postsynaptic 5-HT2 and 5-HT3 receptors without causing unwanted 5-hydroxytryptamine side effects such as nausea and other gastrointestinal symptoms, and therefore mirtazapine is therefore well tolerated.²² The criteria for clinical success are a significant absence of clinical signs and symptoms. Drowsiness, sedation, malaise, increased appetite, and weight gain are common adverse events of mirtazapine, some of which may gradually diminish or disappear. In fact, some FD patients expect mirtazapine to improve sleep, increase appetite, and gain weight.

From a clinical practice perspective, it is very difficult for gastroenterologists to identify depression and anxiety due to a lack of relevant knowledge about mental health. In fact, individuals with anxiety or depression at baseline were more likely to develop FD than participants who did not have anxiety or depression at baseline.²⁹ Compared with previous studies, our study was conducted to observe FD patients, regardless of whether the patients had comorbidities of anxiety or depression, confirming the good therapeutic effect of mirtazapine on FD, and expanding the scope of mirtazapine treatment population.^4,26

Limitations

This trial has several limitations. First, in terms of different clinical subtypes of FD, this study sample is heterogeneous and this may limit our ability to detect differences between groups. Second, participants in this study were screened from a single center, and the 8-week follow-up period may be not long enough to get more outcomes. This trial may have had limited power to detect potentially true effects of mirtazapine with small-size samples. Further validation is needed in large multi-center clinical trials in the future.

Conclusion

This study showed that antidepressant mirtazapine could significantly improve the overall severity of symptoms of dyspepsia (such as individual symptoms of postprandial fullness, early satiation, nausea, and vomiting), gastrointestinal-specific anxiety, quality of life, and increased weight in FD patients, which provided clues to clinicians that mirtazapine may be a good choice for the treatment of FD patients.

Supplemental Material

sj-doc-2-tag-10.1177_17562848241311129 – Supplemental material for Randomized clinical trial: the effects of mirtazapine in functional dyspepsia patients

Supplemental material, sj-doc-2-tag-10.1177_17562848241311129 for Randomized clinical trial: the effects of mirtazapine in functional dyspepsia patients by Lina Cao, Gaozhong Li, Jingmei Cao, Fuxin Li and Wei Han in Therapeutic Advances in Gastroenterology

Supplemental Material

sj-docx-1-tag-10.1177_17562848241311129 – Supplemental material for Randomized clinical trial: the effects of mirtazapine in functional dyspepsia patients

Supplemental material, sj-docx-1-tag-10.1177_17562848241311129 for Randomized clinical trial: the effects of mirtazapine in functional dyspepsia patients by Lina Cao, Gaozhong Li, Jingmei Cao, Fuxin Li and Wei Han in Therapeutic Advances in Gastroenterology

Footnotes

Appendix

Acknowledgements

All the authors thank the subjects who participated in the study, as well as the doctors and nurses involved.

Declarations

ORCID iDs

Lina Cao

Wei Han

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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