Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders (FGIDs), which has been redefined as disorders of gut-brain interactions (DGBI).¹ The dysregulated gut-brain interaction is a central mechanism for generation and recurrence of FD symptoms including epigastric pain and burning, postprandial fullness, and early satiety, which are unexplained after routine examination.^1,2 The current first-line medications, including acid suppressors and prokinetics, mainly modulate the function of the gastrointestinal (GI) tract. Therefore, they are usually unsatisfactory for a considerable proportion of patients. Patients who display persisting FD symptoms for over 6 months and are unresponsive to at least 2 medical treatments (with less than 50% improvement of dyspeptic symptoms), such as antacids, proton pump inhibitors (PPIs), prokinetics, and eradication of Helicobacter pylori, are defined as refractory FD (rFD).^3,4 Clinically, patients with rFD show a high prevalence of psychiatric co-morbidity and are responsive to central neuromodulators.^3,5 Central neuromodulators such as tricyclic antidepressants (TCAs) are recommended as necessary supplements for the treatment of FD, and has shown beneficial effect in relieving dyspeptic symptoms in patients with rFD.^5-9 It has been shown that low to modest dosages of TCAs (25-75 mg/day) could provide the most convincing benefit for treating chronic GI pain and FGIDs in Rome Foundation Working Team Report.¹ Doxepin, as a TCA, has also been recommended in the treatment of FGIDs.¹

Notably, it is a common phenomenon that FD patients on antidepressant therapies often carry stigma, which is defined as social devaluation or discrimination toward a particular population.¹⁰ The stigmatized feelings of patients would get worse when the terms such as ‘brain,’ ‘emotional,’ and ‘psychological’ are used in the clinician-patient communication or appear in the package inserts of medications prescribed for FD.^10,11 Stigma has non-negligible adverse consequences in patients with DGBI, including treatment non-adherence, negative emotion, increased symptoms, and barriers to accessing care.^10,12 It has been reported that poor medication compliance due to stigma mitigates the efficacy of neuromodulators in rFD therapy.¹³ In a previous study, we found that proper explanation of the mechanisms for neuromodulators to patients may alleviate stigma and improve treatment adherence for rFD.¹⁴ These studies indicate that patients’ different comprehensions of therapeutic drugs may influence stigma and thus affect treatment compliance and efficacy in the treatment of DGBI.^2,10,13,14 Exploring more treatment therapies is of great significance to reduce patients’ stigma and improve their medication compliance.

Herbal medicine acquired a deep-rooted cultural identity in Asia, and it is commonly used in the treatment of FD.^15-18 The dissatisfaction with the efficacy of conventional medications has also promoted the global use of herbal medicine in FD as adjunctive therapy recently.^19,20 The mechanisms by which herbal medicine treats FD involve the regulation of emotional status and the function of the digestive system.^21-25 Zhizhu Kuanzhong capsules (ZZKZ; Lonch Group Shanxi Shuang Ren Pharmaceuticals Co. Ltd, Shanxi, China) is a Chinese patent medicine containing 4 herbal medicines, which includes Atractylodes macrocephala (Bai Zhu), Citrus aurantium (Zhi Shi), Bupleurum (Chai Hu), and Hawthorn (Shan Zha). Citrus aurantium has been reported to alleviate anxiety and Bupleurum to alleviate depression.^26,27 In addition, Atractylodes macrocephala and Hawthorn display gastroprotective, anti-inflammatory, and digestive-promoting effects.^18,28-30 Clinical studies have also shown that ZZKZ is beneficial for DGBI including gastroesophageal reflux disease and postprandial distress syndrome (PDS).^31-33 ZZKZ has been recommended for the treatment of FD.¹⁹ However, it is still unknown whether ZZKZ reduces stigma and improves medication adherence in the treatment of rFD. TCAs were proved to be efficacious for FD.³⁴ Therefore, the purpose of this randomized trial is to assess the stigma, medication adherence, and efficacy of ZZKZ versus doxepin in the treatment of rFD.

Ethics

The study was conducted according to the principles of the Declaration of Helsinki and the protocol was approved by the Ethics Committee of the hospital (Approval No. 2018-082). The trial was registered on clinicaltrials.gov (NCT05107999). An informed consent form was obtained from each patient.

Participants

The eligible participants diagnosed as FD were screened by the gastroenterologist at the GI outpatient clinic from February 2021 to February 2022. The inclusion criteria included: (1) met the Rome IV criteria for FD; (2) have sustained symptoms for at least 6 months which are unresponsive to at least 2 medications (histamine-2 blockers, PPIs, prokinetics or H. pylori eradication); (3) absence of H. pylori infection; and (4) without the use of antipsychotics in the past 6 months. The exclusion criteria were: (1) disease that might impair GI function including peptic ulcer, GI cancer, diabetes, scleroderma, heart disease, liver disease, or alcoholism disorders; (2) pregnancy or lactation; (3) a history of abdominal operations; and (4) a history of allergic reaction to any of the medications used in the study.

Study Design

This is a prospective, randomized and single-centered study to explore the complementary therapies to reduce stigma and improve medication compliance in rFD. All the participants had a treatment history of at least 2 of the following medications, including histamine-2 blockers, PPIs, prokinetics and H. pylori eradication, prior to the enrollment of the research. The patients in the doxepin group were given omeprazole (20 mg twice a day) plus doxepin hydrochloride (25 mg tid). The patients in the ZZKZ group were given omeprazole (20 mg bid) plus ZZKZ (2 capsules 3 times a day). Doxepin or ZZKZ was applied after each meal. Omeprazole was applied twice daily, before breakfast and supper. The treatment course was 4 weeks in both groups. Demographic statistics, stigma scales, and dyspeptic symptoms and psychological condition were assessed at baseline. Medication adherence, and scores for stigma, dyspeptic symptoms and psychological condition were evaluated after treatment.

Outcome Measurements

The primary endpoint was medication adherence to doxepin or ZZKZ after the 4-week treatment. The secondary endpoints included the scores for stigma, dyspepsia symptoms, and emotional condition after treatment.

Medication adherence was assessed using medication possession ratio (MPR), defined as the number of drugs taken by the patient during treatment divided by the amount prescribed for 100% compliance.³⁵ MPR values for doxepin or ZZKZ were recorded at the end of treatment. A higher MPR score indicates better compliance.

Stigma attached to the disease was evaluated based on the scores for internalized stigma scale (ISS) and perceived stigma scale (PSS), which was used to assess the severity of internalized stigma (IS) and perceived stigma (PS) in irritable bowel syndrome (IBS) and FD.^12-14,36-39 The ISS contains 4 stigma subscales including alienation, social withdrawal, discrimination, and stereotype endorsement. It has 29 items ranked on a 4-point scale (from 1: strongly disagree to 4: strongly agree). An optional fifth subscale for stigma resistance was not used in this study. The final ISS score was calculated as the average score of all the 24 items. A higher ISS score indicates worse IS (1-2: minimal, 2-2.5: mild, 2.5-3: moderate, 3-4: severe).⁴⁰ The PSS is a 10-item questionnaire with items ranked on a 5-point scale (from 1: never to 5: always).³⁷ The final PSS score is calculated as the average score of the 10 items. A higher score indicates worse PS.

The medication-associated stigma was evaluated using a 4-question scale.⁴¹ Patients were asked to answer the following 4 questions with “yes” or “no” when taking the medicine: (1) I feel ashamed; (2) I do not feel comfortable to tell friends or family; (3) I do not feel okay if people in community know; and (4) I do not want to tell people at job. The proportions of patients answering “yes” for each question was calculated.

The Leeds Dyspepsia Questionnaire (LDQ) scale was applied to assess the frequency and severity of dyspeptic symptoms, including epigastric pain, epigastric burning, postprandial fullness, early satiety, acid reflux, nausea, belch and vomiting.⁴² A higher LDQ score indicates more severe dyspeptic symptoms (0-4: very mild, 5-8: mild, 9-15: moderate, and > 15: severe or very severe).

The Generalized Anxiety Disorder Questionnaire (GAD-7) and Patient Health Questionnaire Depression Scale (PHQ-9) were utilized to assess emotional status.^43,44 The GAD-7 scale consists of 7 items on a 4-point questionnaire (0-3). The final GAD-7 scores are calculated as the sum of the 7 items. The GAD-7 scores of 0-4 are classified as none or minimal anxiety, 5-9 as mild, 10-14 as moderate, and ≥ 15 as severe. The PHQ-9 scale is a 9-item questionnaire with each item has 4 ranks (0-3). The final PHQ-9 scores are calculated as the sum of the 9 items. The PHQ-9 scores of 0-4 are classified as none or minimal depression, 5-9 as mild, 10-14 as moderate, 15-19 as moderately severe, and ≥ 20 as severe depression.

Statistical Methods

MPR, stigma, dyspeptic symptoms, and psychological condition were analyzed based on the per-protocol population. The sample size of 43 patients per arm was calculated based on a 10% difference of MPR values between the 2 groups (0.73 in doxepin group, 0.83 in ZZKZ group) with a significance level of 0.05 (α) and a power of 80% (1 – β) in the 2-sided test. Thus, a minimal of 86 patients were needed in the research. SPSS statistical software package version 24.0 (IBM, Armonk, NY, USA) was applied for statistical analysis. The statistician was masked to group allocation. The difference of post-treatment scores with baseline in each group was assessed using paired t test. Differences of stigma scores or symptom scores between groups were analyzed using unpaired t test. Correlations between medication adherence with stigma scores were assessed with Pearson correlation analyses. The categorical data were analyzed using chi-square test. The categorical data were displayed as n (%). Continuous variables were displayed as mean ± SD. Statistical significance was determined at the P < 0.05 level.

Study Population

A total of 113 patients with rFD were enrolled in the study. The workflow of randomization and treatment is shown in Figure 1. During the treatment, 6 subjects violated the research protocol, 4 were lost to follow-up and 3 withdrew due to adverse reactions. Finally, 100 patients who completed the study were included into data analysis.

Figure 1. Workflow of randomization and treatment in patients with refractory function dyspepsia. ZZKZ, Zhizhu Kuanzhong capsules; ADRs, adverse drug reactions.

The patients had a medication history of at least 2 treatments, including histamine-2 blockers (famotidine), or PPIs (omeprazole, rabeprazole, or lansoprazole), or prokinetic drug (masopride), or H. pylori eradication. Acid-suppressive drugs and prokinetics were commonly used in previous treatments. Before the study, 85.71% (42/49) in the doxepin group and 80.39% (41/51) in the ZZKZ group received famotidine. In addition, 95.92% (47/49) in doxepin group and 94.12% (48/51) in ZZKZ group received PPIs. Also, 79.59% (39/49) in doxepin group and 84.31% (43/51) in ZZKZ group received mosapride. Patients with a history of H. pylori eradication was 10.20% (5/49) in doxepin group and 11.76% (6/51) in ZZKZ group. The baseline clinical characteristics were well balanced in both groups (Table 1).

Table 1 . Demographic and Baseline Clinical Characteristics of the Enrolled Patients in Per-protocol Analysis

Characteristics	Doxepin group (n = 49)	ZZKZ group (n = 51)	P-value
Sex ratio (female/male)	2.26	2.40	0.732
Age (yr)	46.29 ± 12.53	48.37 ± 11.19	0.382
Disease duration (mo)	10.12 ± 2.41	10.25 ± 2.54	0.790
Body mass index (kg/m2)	21.61 ± 1.42	21.95 ± 1.58	0.253
LDQ scores	8.80 ± 1.66	8.73 ± 1.89	0.844
GAD-7 scores	7.20 ± 1.89	7.55 ± 1.82	0.354
PHQ-9 scores	4.82 ± 1.52	4.75 ± 1.28	0.801
ISS scores	2.29 ± 0.74	2.31 ± 0.75	0.890
PSS scores	2.67 ± 0.69	2.69 ± 0.88	0.856
Drug history
Famotidine	42 (85.71)	41 (80.39)	0.347
PPIs	47 (95.92)	48 (94.12)	0.748
Mosapride	39 (79.59)	43 (84.31)	0.581
Eradication of H. pylori	5 (10.20)	6 (11.76)	0.822

ZZKZ, Zhizhu Kuanzhong capsules; LDQ, Leeds Dyspepsia Questionnaire; GAD-7, Generalized Anxiety Disorder Scale; PHQ-9, Patient Health Questionnaire Depression Scale; ISS, internalized stigma scale; PSS, perceived stigma scale; PPI, proton pump inhibitor; H. pylori, Helicobacter pylori.

Data are presented as mean ± SD or n (%).

Medication Adherence

After treatment for 4 weeks, the MPR values for ZZKZ in patients receiving ZZKZ plus omeprazole were significantly higher than that for doxepin in patients receiving doxepin plus omeprazole (0.89 ± 0.01 vs 0.74 ± 0.01, P < 0.001; Fig. 2). These results suggested that ZZKZ prescriptions were more acceptable and better followed than doxepin in patients with rFD.

Figure 2. Medication adherence in patients with refractory functional dyspepsia based on per-protocol population. Medication possession ratio (MPR) for doxepin in patients receiving doxepin plus omeprazole (n = 49) and MPR for Zhizhu Kuanzhong capsules (ZZKZ) in patients receiving ZZKZ plus omeprazole (n = 51). Data are presented as mean ± SD. ***P < 0.001.

Stigma of Patients After Treatment

After the 4-week treatment, patients treated with ZZKZ plus omeprazole showed significantly decreased ISS scores (2.31 ± 0.75 vs 2.04 ± 0.54, P = 0.034; Fig. 3A) and PSS scores (2.69 ± 0.88 vs 1.97 ± 0.42, P < 0.001; Fig. 3B) compared to baseline. However, patients treated with doxepin plus omeprazole showed elevated ISS scores (2.30 ± 0.74 vs 2.76 ± 0.84, P < 0.01; Fig. 3A) and PSS scores compared to baseline (2.67 ± 0.69 vs 2.98 ± 0.55, P = 0.013; Fig. 3B). Moreover, the post-treatment ISS scores of patients were significantly lower in ZZKZ group than in doxepin group (2.04 ± 0.54 vs 2.76 ± 0.84, P < 0.001; Fig. 3A). The post-treatment PSS scores of patients were also significantly lower in ZZKZ group than in doxepin group (1.97 ± 0.42 vs 2.98 ± 0.55, P < 0.001; Fig. 3B). In addition, a majority of patients showed decreased stigma scores after treatment in ZZKZ group, while increased in doxepin group (Table 2). The percentage of patients with decreased stigma scores in ZZKZ group was significantly higher than that in doxepin group (ISS: 78.43% vs 8.16%, P < 0.01; PSS: 72.55% vs 26.53%, P < 0.01; Table 2).

Table 2 . Alterations of Stigma Scores After Treatment

Stigma scales	Change of scores	Doxepin group (n = 49)	ZZKZ group (n = 51)
ISS	Decreased	4 (8.16)	40 (78.43)a
	Unaltered	2 (4.08)	6 (11.76)
	Increased	43 (87.76)	5 (9.80)a
PSS	Decreased	13 (26.53)	37 (72.55)a
	Unaltered	3 (6.12)	3 (5.88)
	Increased	33 (67.35)	11 (21.57)a

^aP < 0.01 (χ² test).

ZZKZ, Zhizhu Kuanzhong capsules; ISS, internalized stigma scale; PSS, perceived stigma scale.

Data are presented as n (%).

Figure 3. Scores for internalized stigma scale (ISS) and perceived stigma scale (PSS) in patients with refractory functional dyspepsia (rFD). (A) ISS and (B) PSS scores before and after treatment in doxepin group (n = 49) and Zhizhu Kuanzhong capsul (ZZKZ) group (n = 51). Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001.

ISS and PSS cannot distinguish between medication-associated stigma and disease-associated stigma. We thus applied a 4-question scale to assess medication-associated stigma clearly in rFD patients. In ZZKZ group, 3 of 51 subjects (5.88%) felt ashamed when taking the drug, while 35 of 49 subjects (71.43%) in doxepin group felt ashamed when taking doxepin (P < 0.001). Only 2 subjects (3.92%) felt uncomfortable when telling others about taking ZZKZ, while 31 cases (63.27%) felt uncomfortable when telling others about taking doxepin (P < 0.001). Only 1 subject (1.96%) in ZZKZ group did not feel okay when people in community knew ZZKZ, while 46 patients (93.88%) in doxepin group answering “yes” for this question, which was significantly higher than that in ZZKZ group (1.96% vs 93.88%, P < 0.001; Table 3). 2 cases (3.92%) in ZZKZ group did not want to tell people at job, while the rate of patients answering “yes” for this question in doxepin group (47/49, 95.92%) was significantly higher than that in ZZKZ group (95.92% vs 3.92%, P < 0.001; Table 3). It seemed that 1.96%-5.88% of patients showed stigma attached to herbal medicine, while 63.27%-95.92% of patients showed stigma attached to neuromodulators.

Table 3 . Medication-associated Stigma After Treatment

Questions	Doxepin group (n = 49)	ZZKZ group (n = 51)
Feel ashamed when taking the drug	35 (71.43)	3 (5.88)a
Feel uncomfortable when telling others about taking the drug	31 (63.27)	2 (3.92)a
Do not feel okay if people in community know the drug	46 (93.88)	1 (1.96)a
Do not want to tell people at job	47 (95.92)	2 (3.92)a

^aP < 0.001 (χ² test).

ZZKZ, Zhizhu Kuanzhong capsules.

Data are presented as n (%).

Correlations Between Stigma and Medication Adherence

We next analyzed the correlations between patients’ stigma and MPR in ZZKZ or doxepin groups. The results showed that the MPR values for doxepin was negatively correlated with post-treatment ISS scores (r = –0.74, P < 0.001; Fig. 4A) and PSS scores (r = –0.58, P < 0.001; Fig. 4C) in patients receiving doxepin plus omeprazole treatment. The MPR values for ZZKZ were also negatively correlated with post-treatment ISS scores (r = –0.53, P < 0.001; Fig. 4B) and PSS scores (r = –0.56, P < 0.001; Fig. 4D) in patients receiving ZZKZ plus omeprazole treatment.

Figure 4. Correlation between medication possession ratio (MPR) with stigma scores. Correlation between MPR values for doxepin (n = 49) with (A) internalized stigma scale (ISS) scores and (C) perceived stigma scale (PSS) scores. Correlations between MPR values for Zhizhu Kuanzhong capsules (ZZKZ) (n = 51) with (B) ISS scores and (D) PSS scores.

Treatment Efficacy

After 4-week treatment, the LDQ scores of patients in doxepin group and ZZKZ group decreased significantly compared to respective baseline (doxepin group: 8.80 ± 1.66 vs 4.43 ± 0.96, P < 0.001; ZZKZ group: 8.73 ± 1.89 vs 4.47 ± 1.08, P < 0.001; Fig. 5A). Significant difference was not observed in post-treatment LDQ scores of patients between the two groups (4.43 ± 0.96 vs 4.47 ± 1.08, P = 0.838) (Fig. 5A). Specifically, epigastric pain or burning was significantly improved in both groups compared to baseline (doxepin group: 1.90 ± 0.71 vs 0.90 ± 0.37 for pain and 1.53 ± 0.82 vs 0.79 ± 0.46 for burning; ZZKZ group: 1.94 ± 0.70 vs 1.00 ± 0.40 for pain and 1.41 ± 0.78 vs 0.80 ± 0.45 for burning; all P < 0.001). Early satiety was improved in both groups compared to baseline (doxepin group: 1.33 ± 0.83 vs 0.78 ± 0.42; ZZKZ group: 1.39 ± 0.55 vs 0.72 ± 0.49; P < 0.001). Postprandial fullness was improved in both groups compared to baseline (doxepin group: 1.55 ± 0.65 vs 0.94 ± 0.32; ZZKZ group: 1.76 ± 0.55 vs 0.96 ± 0.28; P < 0.001). Other symptoms such as acid reflux and nausea were also improved in both groups compared to baseline (doxepin group: 1.84 ± 0.59 vs 0.80 ± 0.46 for acid reflux and 0.31 ± 0.51 vs 0.08 ± 0.28 for nausea; ZZKZ group: 1.67 ± 0.68 vs 0.86 ± 0.40 for acid reflux and 0.25 ± 0.48 vs 0.04 ± 0.20 for nausea; P < 0.001 for acid reflux and P < 0.01 for nausea). Vomiting and belch only appeared in several rFD patients, and no significant difference was observed after treatment compared with baseline of each group. No significant difference was observed in the improvement of the above symptoms between 2 groups (Supplementary Figure). Obvious symptom recurrence was not observed in a 4-week observation period after completing ZZKZ treatment.

Figure 5. Treatment efficacy in patients with refractory functional dyspepsia. (A) Dyspepsia symptom scores, (B) anxiety scores, and (C) depression scores before and after treatment in doxepin group (n = 49) and Zhizhu Kuanzhong capsules (ZZKZ) group (n = 51). LDQ, Leeds Dyspepsia Questionnaire; GAD-7, Generalized Anxiety Disorder Questionnaire; PHQ-9, Patient Health Questionnaire Depression Scale. Data are presented as mean ± SD. **P < 0.01, ***P < 0.001.

In addition, the GAD-7 scores (for assessment of anxiety) of patients in the 2 groups were significantly decreased after treatment compared to baseline (doxepin group: 7.20 ± 1.89 vs 4.10 ± 1.45, P < 0.01; ZZKZ group: 7.55 ± 1.82 vs 4.14 ± 1.17, P < 0.01). There was no significant difference in GAD-7 scores of patients between the two groups after treatment (4.10 ± 1.45 vs 4.14 ± 1.17, P = 0.894) (Fig. 5B). The PHQ-9 scores (for assessment of depression) of patients in the two groups were significantly relieved after treatment compared to baseline (doxepin group: 4.82 ± 1.52 vs 2.55 ± 1.23, P < 0.01; ZZKZ group: 4.75 ± 1.28 vs 2.77 ± 1.38, P < 0.01). There was no significant difference in PHQ-9 score of patients between the two groups after treatment (2.55 ± 1.25 vs 2.77 ± 1.38, P = 0.416 (Fig. 5C).

Safety Analyses

Adverse reactions during treatment were reported in 6.12% (3/49) of patients in doxepin group and 3.92% (2/51) of patients in ZZKZ group. No significant difference was found in the overall rate of adverse reactions between 2 groups. Sleep disturbances were observed in doxepin group with 3 patients (6.12%) reporting drowsiness. The observed adverse reactions in ZZKZ group were GI symptoms with 2 patients (3.92%) reporting constipation and dry mouth. All these reactions were mild and resolved spontaneously at the end of the study. No life-threatening adverse events were observed in 2 groups.

The dysregulated gut-brain interaction plays a critical role in the pathogenesis of FD.² The current treatment options are limited and far from optimal. Clinical evidence has shown the necessity of neuromodulators for the treatment of FD.^1,45 However, stigma attached to the disease and/or neuromodulators may lead to treatment non-compliance and greatly hinder treatment efficacy which limits the clinical application of neuromodulators.^10,13,38,46 There is a lack of appropriate strategies to alleviate stigma of FD patients, except by improving clinician-patient communication, which has been published in our previous work.¹⁴ The concerns and stigma associated with neuromodulators promote the use of complementary or alternative medicine in FD with psychological symptoms, such as herbal medicine.^17,19,47,48 Herbal medicine has been reported efficacious in improving dyspeptic symptoms in multiple studies.^{15-17,20,23,24,31} However, the influence of herbal medicine on stigma and medication adherence in the treatment of rFD is still unknown. This randomized controlled trial shows that ZZKZ is superior to doxepin (a TCA) in reducing stigma and medication non-adherence, with comparable efficacy in improving dyspeptic symptoms and psychological condition of patients with rFD. These results indicated that ZZKZ may be used as an alternative or adjunctive treatment for rFD.

In this study, we observed that ZZKZ significantly reduced the disease- and medication-associated stigma in patients with rFD, with concurrent improvement of medication adherence compared to doxepin. The PSS and ISS scores of patients were significantly decreased in ZZKZ group while increased in doxepin group after a 4-week treatment. As PSS and ISS cannot clearly reflect the differences between stigma attached to ZZKZ or doxepin, we applied a 4-question questionnaire for assessment of medication-related stigma.⁴¹ The results showed that only 1.96-5.88% of patients showed stigma related with ZZKZ while 63.27-95.92% of patients showed stigma related with doxepin, suggesting that patients were more acceptable with taking ZZKZ than doxepin. Taken together, the above results indicated that ZZKZ, as a kind of herbal formula, could significantly improve stigma attached to disease and medications compared to psychiatric drugs (such as doxepin). Notably, we observed that patients displayed better medication adherence to ZZKZ than to doxepin. In addition, similar to the results of our previous studies, the MPR values to ZZKZ or doxepin were negatively correlated with post-treatment ISS and PSS scores, indicating that the improvement of medication adherence may be associated with the reduction of stigma.^13,14 The possible reasons why patients in ZZKZ group showed higher compliance and less stigma are probably because that Chinese patients generally accept that herbal medicine can act integratedly to improve the function of digestive system and emotional status rather than act as psychotropic medications.¹⁵ A proportion of patients in doxepin group holding the stigmatized feelings are often strongly reluctant to be labelled as people with “mental disease” or take “psychiatric medicines”, which was also reported in other studies about antidepressant therapy.^10,13 For them, ZZKZ may serve as a complementary medication and provide the optimal treatment efficacy.

The formula of ZZKZ contains Citrus aurantium (with anxiolytic activity) and Bupleurum (with antidepressant activity), and it has been shown to be beneficial in the treatment of dyspeptic symptoms.^26,27,31,33 In the present study, patients showed relieved dyspeptic symptoms (such as epigastric pain, epigastric burning, postprandial fullness, and early satiety) and emotional distress after receiving ZZKZ or doxepin plus omeprazole treatment. The LDQ, GAD-7, and PHQ-9 scores of patients significantly decreased after treatment in both ZZKZ and doxepin groups, and there was no significant difference in the post-treatment scores between the 2 groups. These results suggested that ZZKZ displayed noninferior effect compared to doxepin in improving dyspeptic symptoms and emotional condition. A small proportion (3.92%) of patients receiving ZZKZ treatment showed mild adverse effects including constipation and dry mouth. Similarly, one previous research reported that the most concerned adverse effects of ZZKZ were GI symptoms (3.1%), including abdominal pain, diarrhea and nausea in patients with PDS.³¹ Another research reported no adverse events in patients with gastroesophageal reflux disease receiving ZZKZ combined with electroacupuncture treatment.³² The different manifestations of adverse reactions may be associated with the patient composition with overlapping symptoms in our research. Besides, no severe adverse events of ZZKZ have been reported by the China Food and Drug Administration.³¹ Therefore, ZZKZ may serve as a substitution or complementary medication of neuromodulators for patients with rFD, especially for those holding severe stigmatized attitudes towards antidepressants.¹⁰

This study has limitations. Firstly, there may exist potential subjective bias as it is not a double-blind trial. Secondly, it was conducted in a Chinese population where people hold a deep-rooted cultural identity to herbal medicine. Perhaps it is not applicable to other races who are not familiar with herbal medicine or share different attitudes towards traditional/local remedies.⁴⁹ Thirdly, only 1 kind of TCAs (doxepin) was selected as the control in this study. The curative effect of other neuromodulators on rFD may be different. Besides, we did not distinguish between EPS and PDS in the group allocation as many patients with rFD displayed overlapping symptoms. Lastly, the medication history of rFD patients was broad, which may increase the heterogeneousness of the patient composition in the research.

In conclusion, the present study suggests that ZZKZ is superior to doxepin in reducing stigma and drug non-adherence, with comparable efficacy in improving dyspeptic symptoms and psychological conditions of patients with rFD. It could be considered as an alternative or supplemental treatment option for patients with rFD.

Note: To access the supplementary figure mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm22145.

The work was supported by the National Natural Science Foundation of China (Grant Nos. 82170554 and 81970473 to Sheng-Liang Chen, and 81970472 to Xiu-Juan Yan).

None.

Qian-Qian Wang, Li Cheng, Xiu-Juan Yan, Ping Xu, and Hong-Yi Qiu performed the study; Bo Wang and Bi-Yu Wu collected and analyzed the data; Qian-Qian Wang, Xiu-Juan Yan, and Sheng-Liang Chen prepared the manuscript: and Sheng-Liang Chen designed the study and reviewed the manuscript.