DOI:https://doi-xx.org/1050/17821990965864

[Funding]: Sichuan Province Traditional Chinese Medicine Administration Research Project (Grant No. 2023MS402)

[First Author]: Chen Wei, Wang li  Attending Physician, currently engaged in clinical research on psychosomatic disorders. Tel: 18113663421. E-mail: 1515603786@qq.com

[Corresponding Author]: Jian Xuesong, Associate Chief Physician, currently engaged in clinical research on psychosomatic disorders. Tel: 13398141530. E-mail: 1608575726@qq.com

Chen Wei¹, Wang Li¹, Ke Chengren, Yan Menglin, Li Jiaxin, Luo Kerun, Jian Xuesong*

(Traditional Chinese Medicine Hospital of Meishan, Address：No.9, North Section of Mindong Avenue, Dongpo District, Meishan, Sichuan Province, China (620010))

Abstract

Objective: To investigate the clinical efficacy and adverse effects of Yin-nourishing and dryness-moistening therapy combined with paroxetine tablets in treating dry mouth symptoms of the Yin deficiency and fluid insufficiency pattern in patients with anxiety disorder.

Methods: Hospitalized anxiety disorder patients from the Psychosomatic Diseases Department of Meishan Traditional Chinese Medicine Hospital were recruited as study subjects. Patients were randomly divided into an observation group and a control group, with 50 patients in each group. Both groups received oral paroxetine tablets with an initial dose of 10 mg/d, increased to 20–40 mg/d within 2 weeks based on tolerance, with a maximum daily dose not exceeding 40 mg, taken after breakfast. The observation group additionally received 200 mL of Yin-nourishing and dryness-moistening herbal decoction three times daily (tid). The control group additionally received 200 mL of placebo (containing 5% active herb and flavoring agent) tid. The total treatment duration was 4 consecutive weeks. The Self-Rating Anxiety Scale (SAS) was used to assess anxiety levels before treatment and at the end of weeks 2 and 4. Dry mouth severity was assessed using a dry mouth grading scale and by monitoring saliva secretion volume. Adverse reactions and their management were recorded at the end of weeks 2 and 4.

Results: A total of 40 cases in the observation group and 36 cases in the control group were included in the final analysis. Dry mouth improvement was significantly greater in the observation group after treatment, with a significantly higher increase in saliva secretion compared to the control group (P < 0.01). The main adverse reactions in the observation group were constipation (12.5%) and nausea (10.0%); in the control group, the main adverse reactions were dry mouth (16.7%) and nausea (13.9%).

Conclusion: Yin-nourishing and dryness-moistening therapy combined with paroxetine tablets can effectively alleviate dry mouth symptoms of the Yin deficiency and fluid insufficiency pattern, improve anxiety symptoms, and demonstrates good safety in patients with anxiety disorder.

Keywords: Yin-nourishing and dryness-moistening therapy; Paroxetine tablets; Anxiety disorder; Yin deficiency and fluid insufficiency; Dry mouth

Introduction

Non-organic dry mouth is a common accompanying symptom of anxiety disorder with high clinical incidence, causing serious distress to patients. Studies have found its clinical prevalence to be 70.51% [1]. Meanwhile, the anti-anxiety medications currently in use often induce adverse reactions such as dry mouth, nausea, and constipation during treatment, with some patients experiencing oral mucosal dryness, cracking, and hoarseness, and in severe cases, difficulty eating. The pronounced somatic symptoms are difficult for patients to tolerate, and combined with the long duration of medication and slow onset of action, many patients fail to persist until the drug takes effect, either discontinuing treatment due to poor compliance or intolerance to adverse reactions, thus seriously compromising clinical outcomes. Currently, there is very little domestic or international research on the use of Chinese herbal medicine to treat non-organic dry mouth symptoms in anxiety disorder patients. Domestic treatment protocols predominantly favor Western pharmacotherapy, but the efficacy in anxiety disorder patients remains without definitive conclusions. Traditional Chinese Medicine (TCM) syndrome differentiation and treatment of dry mouth from various causes has a long history, rich clinical experience, and confirmed therapeutic efficacy. Investigating whether it is effective for the non-organic dry mouth that accompanies anxiety disorder is of great significance.

In the framework of TCM theory, dry mouth belongs to the category of “dryness pathogen” (燥邪) [2–3], and its etiology is primarily attributed to Yin deficiency with fluid insufficiency and dysregulation of qi movement. This study was designed to evaluate a Yin-nourishing and dryness-moistening herbal decoction combined with paroxetine tablets for the treatment of non-organic dry mouth in anxiety disorder patients. The aim is to fill the gap in relevant clinical research, overcome the limitations of Western pharmacotherapy alone, optimize treatment protocols, enrich the existing literature, provide empirical support for TCM treatment of non-organic dry mouth in anxiety disorder, and explore new directions for syndrome-differentiation-based TCM treatment of this condition.

1. Materials and Methods

1.1 Study Design and Blinding

This study adopted a randomized, double-blind, controlled clinical trial design. The specific protocol was as follows: ① Randomization: eligible patients were allocated in a 1:1 ratio to the observation or control group using a computer-generated random number table. ② Double-blinding: the study medication (Yin-nourishing and dryness-moistening decoction) and the placebo (containing 5% active herb and flavoring agent) were uniformly prepared, packaged, and numbered by the pharmacy department, which was independent of the research team. Both liquids were formulated to be as identical as possible in appearance (color, clarity), odor, and taste. All medication packaging bags were labeled only with a randomly generated unique serial number. The correspondence between serial numbers and group assignments was sealed and kept by a dedicated pharmacist until the end of the study. Throughout the study, researchers responsible for patient enrollment, intervention implementation, efficacy assessment, and safety evaluation, as well as all participants, were blinded to group assignment (i.e., unaware of whether the liquid taken was herbal decoction or placebo). Medication distribution was carried out by designated nurses not involved in efficacy evaluation, based on random serial numbers. After the trial concluded, all observational data were entered into the established database. Following data lock-down by professional statisticians, a first-level unblinding was conducted to identify the treatment and control groups for baseline characteristic analysis. After preliminary statistical analysis, a second-level unblinding was performed to match interventions, followed by further statistical analysis of the data.

1.2 Study Subjects

Patients hospitalized in the Psychosomatic Diseases Department of Meishan Traditional Chinese Medicine Hospital between January 2023 and June 2024 who met the study inclusion criteria were enrolled.

1.3 Inclusion Criteria

① Age 18–40 years; ② Signed informed consent; ③ Study data approved by the Ethics Committee; ④ Assessed by two or more psychiatrists with attending physician qualification or above; ⑤ Both the observation and control groups were required to meet the following conditions: 1) Met the diagnostic criteria for anxiety disorder according to the International Classification of Diseases, 10th Revision (ICD-10); 2) SAS standard score ≥ 50; 3) Presented with dry mouth symptoms of the Yin deficiency and fluid insufficiency pattern (primary symptoms: dry mouth and dry throat; secondary symptoms: heat sensation in the palms and soles, night sweats, red tongue with scant coating, and thready rapid pulse, consistent with the Yin deficiency and fluid insufficiency syndrome).

1.4 Exclusion Criteria

① Age below 18 or above 40 years; ② Previous diagnosis of other mental disorders; ③ Meeting ICD-10 criteria for other psychiatric conditions; ④ Comorbid other psychiatric disorders; ⑤ History of substance abuse; ⑥ Presence of other serious somatic diseases, including organic brain disease, major organ dysfunction (heart, liver, kidney), or malignant tumors; ⑦ History of epileptic seizures, extrapyramidal reactions, endocrine disorders, or oral diseases; ⑧ Previous ineffectiveness or intolerance to paroxetine (including adverse reactions such as extrapyramidal symptoms).

1.5 Criteria for Discontinuation

① Occurrence of serious adverse reactions; ② Protocol violation; ③ Participant request to withdraw; ④ Development of serious organic disease or other psychiatric illness during the study; ⑤ Need to change medication or transfer to another ward due to disease progression; ⑥ Exclusion of participants with severe suicidal tendencies or personality disorders.

1.6 Interventions

Observation group: Paroxetine tablets (Leyou, Lot No. YBH06212017, 20 mg/tablet) at 20–40 mg/d combined with Yin-nourishing and dryness-moistening herbal decoction (Rehmannia root [生地] 30 g, Coastal glehnia root [北沙参] 30 g, Ophiopogon root [麦门冬] 30 g, etc.), one decoction per day, divided into three oral doses. Control group: Paroxetine tablets 20–40 mg/d combined with placebo (containing 5% active herb and flavoring agent), administered in the same manner as the observation group. The treatment course was 4 weeks. During this period, other anti-anxiety medications were prohibited. Benzodiazepines could be used selectively at night based on individual sleep conditions, but continuous use was not to exceed 2 weeks.

1.7 Outcome Measures

Anxiety level: assessed using the SAS scale; scoring criteria: no anxiety (< 50), mild anxiety (50–60), moderate anxiety (61–70), severe anxiety (> 70).

Dry mouth severity: graded on a 0–4 scale (Grade 0: no dry mouth; Grade 1: mild dry mouth upon waking only; Grade 2: persistent mild dry mouth not affecting speech or eating; Grade 3: persistent moderate dry mouth requiring water intake while speaking or eating; Grade 4: persistent severe dry mouth with burning sensation in the mouth, difficulty swallowing, and need for water at all times).

Saliva secretion volume: measured by the cotton swab method [4] before treatment and at the end of weeks 2 and 4, with incremental changes calculated. (Specific procedure: After the patient rinsed the mouth with clean water, residual saliva was absorbed with a cotton swab. Three pre-weighed dry cotton swabs were then placed under the tongue and bilaterally at the parotid glands. The patient was instructed not to swallow saliva. After 2 minutes, the swabs were removed, residual saliva on the tongue surface and sublingual fossa was absorbed, and the swabs were weighed [Meilen electronic balance, MT201, Shenzhen Meifu Electronics Co., Ltd., China]).

Adverse reactions: occurrence and management of adverse reactions were recorded at the end of weeks 2 and 4.

1.8 Efficacy Criteria

Anxiety level: According to the Chinese Classification of Mental Disorders (CCMD-3): Clinical cure: symptoms and signs essentially disappeared, SAS score reduction rate > 75%. Marked improvement: symptoms and signs markedly improved, SAS score reduction rate 50%–75%. Improvement: symptoms and signs improved, SAS score reduction rate 25%–50%. No improvement: symptoms and signs with no significant change, SAS score reduction rate < 25%. (SAS score reduction rate % = [pre-treatment score − post-treatment score] / pre-treatment score × 100%).

Dry mouth severity: According to relevant literature [5]: Effective: dry mouth grade decreased and/or saliva secretion increased. Ineffective: both dry mouth grade and saliva volume remained at pre-treatment levels.

1.9 Statistical Methods

This study adopted the Full Analysis Set (FAS) [6] approach, eliminating missing data using the most appropriate method to reduce information bias due to data missingness. All data were analyzed using SPSS 21.0 software. Continuous variables are expressed as mean ± standard deviation; Student’s t-test was used when data conformed to normal distribution with homogeneous variance, and corrected t-test was used when variances were unequal. Categorical variables were analyzed using the chi-square (χ²) test. P < 0.05 was considered statistically significant.

2. Results

2.1 Patient Flow Diagram

A total of 100 patients were enrolled based on inclusion criteria. Using stratified randomization, patients were equally allocated to the observation and control groups. A total of 24 patients were withdrawn due to adverse reactions, poor compliance, or other reasons, including 10 from the observation group and 14 from the control group. The final analysis included 76 patients: 40 in the observation group (18 males, 22 females) and 36 in the control group (16 males, 20 females) (see Figure 1).

Figure 1. Patient Flow Diagram [Observation group: Paroxetine + Herbal decoction; Control group: Paroxetine + Placebo; 100 eligible patients enrolled; 1:1 randomization after informed consent; 40 cases included in analysis (18 M, 22 F), 10 withdrawn; 36 cases included in analysis (16 M, 20 F), 14 withdrawn]

2.2 Comparison of Baseline Characteristics

Among the patients included in the analysis, the mean age of the observation group was (29.44 ± 6.56) years and that of the control group was (28.98 ± 7.12) years. At baseline, there were no statistically significant differences between the two groups in age, sex distribution, or paroxetine dosage (P > 0.05), indicating comparability of baseline characteristics (see Table 1).

Table 1. Comparison of Baseline Characteristics Between the Two Groups

2.3 Comparison of Primary Outcomes After Treatment

2.3.1 Saliva Secretion Increment

Compared with the control group, the saliva secretion increments in the first 2 weeks, the second 2 weeks, and the total increment over 4 weeks were all significantly higher in the observation group, with statistically significant differences (P < 0.01). The saliva increment in the first 2 weeks was slightly higher than in the second 2 weeks in both groups, but there was no statistically significant difference between the two time periods within each group (P > 0.05) (see Table 2).

Table 2. Comparison of Saliva Secretion Increments Between the Observation and Control Groups (x̄ ± s, g)

Note: Increment 1 = saliva secretion increment in weeks 1–2; Increment 2 = saliva secretion increment in weeks 3–4; Total increment = total saliva secretion increment at study end; △P < 0.01 vs. control group.

2.3.2 SAS Score Reduction

In the observation group, anxiety score reduction was not prominent in the first 2 weeks (7 cases in the “effective” category). In the second 2 weeks, reductions increased markedly: 14 cases showed marked improvement and 21 cases showed improvement. By study end, all 40 cases (100%) showed effective anxiety reduction: 1 clinical cure, 20 marked improvement, and 19 improvement. In the control group, anxiety score reduction was minimal in the first 2 weeks (1 case effective). In the second 2 weeks there was no notable increase, and the reduction rate actually declined. By study end, only 15 cases in the control group showed improvement. Overall, the marked improvement rate of SAS score reduction in the observation group was significantly superior to the control group at study end (see Table 3).

Table 3. SAS Score Reduction in the Observation and Control Groups

Note: T1: SAS score reduction rate in weeks 1–2; T2: SAS score reduction rate in weeks 3–4; T3: SAS score reduction rate at study end compared with pre-study baseline.

2.3.3 Number of Patients with Dry Mouth Grade Reduction

In the observation group, at the end of week 2, 37 patients showed a reduction in dry mouth grade, of whom 14 reduced by 2 grades and 23 reduced by 1 grade; at the end of week 4, 34 patients showed a reduction, with 18 reducing by 2 grades and 16 by 1 grade. In the control group, at the end of week 2, 23 patients showed a reduction, all by 1 grade; at the end of week 4, 15 patients showed a reduction, with 1 reducing by 2 grades and 14 by 1 grade. Overall, 18 patients (45.0%) in the observation group showed a 2-grade reduction in dry mouth at the end of week 4, significantly superior to the control group (1 patient, 2.8%) (see Table 4).

Table 4. Number of Patients with Dry Mouth Grade Reduction

2.3.4 Safety Analysis

In the observation group, the primary adverse reactions were constipation (5 cases, 12.5%) and nausea (4 cases, 10.0%). In the control group, dry mouth and constipation were more prominent, with dry mouth occurring in 6 cases (16.7%) and constipation in 5 cases (13.9%) (see Table 5).

Table 5. Comparison of Adverse Reaction Incidence [n (%)]

3. Discussion

The results of this study demonstrate that the observation group was significantly superior to the control group in saliva secretion volume, improvement in dry mouth symptom grading, and anxiety relief (SAS scores), indicating that Yin-nourishing and dryness-moistening therapy not only effectively alleviates the dry mouth side effects induced by anti-anxiety medication, but may also synergistically improve the primary anxiety symptoms by regulating the state of Yin deficiency and fluid insufficiency.

3.1 Mechanisms of Dry Mouth Symptom Improvement

This study demonstrates that Yin-nourishing and dryness-moistening therapy combined with paroxetine tablets can significantly improve dry mouth symptoms in anxiety disorder patients, a mechanism that may be related to the multi-target regulatory effects of Chinese herbal medicine. On one hand, Rehmannia root (生地) in the formula is sweet and cold, nourishing Yin and generating fluids; Ophiopogon root (麦门冬) is sweet and slightly cold, nourishing Yin, moistening the lungs, and benefiting the stomach to generate fluids; Coastal glehnia root (北沙参) is sweet and slightly cold, nourishing Yin, clearing the lungs, and benefiting the stomach. These three herbs serve as the sovereign drugs and directly replenish the deficiency of Yin fluids. Anxiety disorder itself and paroxetine treatment can both lead to sympathetic nervous system activation or impaired cholinergic system function, inhibiting salivary gland secretion. The Yin-nourishing and dryness-moistening herbs may antagonize this inhibitory effect through pathways such as regulating autonomic nervous function balance, improving local microcirculation, or potentially influencing salivary gland M3 receptor function, thereby promoting saliva secretion. On the other hand, patients with anxiety disorder frequently present with “qi movement dysregulation”; the formula incorporates Citron (香橼) to soothe the liver and regulate qi, and Atractylodes (白术) to invigorate the spleen and replenish qi, helping to restore the middle jiao’s function of transforming and transporting fluids and promoting their generation and distribution — consistent with the core pathomechanism of “Yin deficiency with fluid insufficiency and qi movement dysregulation.” The continuous increase in saliva volume data and the marked improvement in dry mouth severity powerfully support the regulatory effect of Chinese herbal medicine on salivary gland function.

3.2 Synergistic Effect on Anxiety Symptom Improvement

Regarding anxiety relief, the effective and marked improvement rates of SAS score reduction in the observation group were significantly higher than those in the control group, with improvements becoming more pronounced over time. This suggests that Chinese herbal medicine may have a synergistic improving effect on primary anxiety symptoms, possibly related to the cooperative modulation of neurotransmitters and the alleviation of anxious mood. Although the control group also showed some improvement in the later phase, the marked improvement rate was extremely low — mainly at the “improvement” level — and dry mouth side effects were more prominent, highlighting the advantages of the observation group’s regimen.

3.3 Safety Analysis and Value of Protocol Optimization

Safety analysis revealed a higher incidence of dry mouth in the control group (16.7%), which is highly consistent with the known side effect profile of paroxetine in inhibiting saliva secretion. The observation group significantly reduced the incidence of dry mouth (observation group 0% vs. control group 16.7%) by combining Yin-nourishing and dryness-moistening Chinese medicine, suggesting that the combined protocol effectively antagonizes this key side effect of paroxetine, substantially improving tolerability. This is particularly beneficial for patients who are inherently susceptible to medication-induced dry mouth or who have poor tolerance to dry mouth symptoms, thereby enhancing treatment adherence and quality of life. No serious adverse reactions such as extrapyramidal symptoms were reported, which is related to the strict exclusion criteria. The higher incidence of nausea in the observation group may be related to individual variation in tolerance to the taste of herbal decoctions.

3.4 Limitations and Future Directions

This study also has certain limitations. These include a relatively small sample size (76 cases in the final analysis), which may reduce statistical power for subgroup analyses; a short follow-up period (only 4 weeks), making it impossible to evaluate the long-term stability of efficacy and the sustained regulatory effects of Chinese medicine; the absence of a Chinese medicine-only group, making it difficult to fully distinguish the direct effects of Chinese medicine on anxiety from its indirect effects (via dry mouth improvement and enhanced comfort); and a lack of in-depth exploration of the correlation between changes in saliva secretion volume and specific neurotransmitter or inflammatory factor levels. Future research should expand sample sizes, extend treatment duration with longer follow-up intervals, explore the addition of a Chinese medicine-only group, and attempt to integrate modern detection methods to elucidate the specific biological mechanisms by which Yin-nourishing and dryness-moistening Chinese medicine improves dry mouth and anxiety symptoms — particularly the related pathways through which it regulates salivary secretion and neuropsychiatric activity.

4. Conclusion

Yin-nourishing and dryness-moistening therapy combined with paroxetine tablets can effectively alleviate dry mouth symptoms of the Yin deficiency and fluid insufficiency pattern, improve anxiety symptoms, and demonstrates good safety in patients with anxiety disorder, providing new insights for integrated traditional Chinese and Western medicine treatment.

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