Efficacy of Traditional Chinese Medicine psychosomatic integration therapy for subthreshold depression: a multicenter randomized controlled trial

Abstract

OBJECTIVE:

To evaluate the efficacy of Traditional Chinese Medicine (TCM) psychosomatic integration therapy in treating subthreshold depression (SD).

METHODS:

A multicenter randomized controlled trial was conducted. Eligible participants were evaluated by physicians and randomly assigned to either the intervention or control group. The intervention group received group psychotherapy, Jue tune music therapy, and Yuleyin oral formula (郁乐饮). The control group received only group psychotherapy. The intervention period lasted 12 weeks, followed by a 12-week follow-up. The primary outcome was the Center for Epidemiologic Studies Depression Scale (CES-D) score at week 12. Secondary outcomes included dropout rate, scores of the Hamilton Anxiety Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD-17) at week 12, and CES-D scores at weeks 4, 8, 16, 20, and 24.

RESULTS:

A total of 505 patients were randomly allocated to the two groups, and 496 participants [77% female; (38 ± 16) years] were included in the final analysis. The primary outcome showed no statistically significant difference in CES-D scores between the intervention and control groups at week 12 (P > 0.05). However, the intervention group exhibited significant reductions in CES-D scores at weeks 4, 8, 12, 16, 20, and 24 compared to baseline, and at week 24 compared to week 12 (P < 0.0001). The control group also showed significant reductions in CES-D scores at weeks 4 and 8 during the intervention period (P < 0.0001). Although no significant differences were observed between groups at each specific time point, the intervention group showed a more consistent downward trend. Additionally, both HAMD and HAMA scores significantly decreased from baseline to week 12 in both groups (P< 0.0001).

CONCLUSIONS:

TCM psychosomatic integration therapy, which includes group psychotherapy, Jue tune music therapy, and Yuleyin oral formula, may be effective in improving symptoms of SD, with good safety and feasibility. The complete TCM intervention demonstrated better long-term effectiveness than group psychotherapy alone. Further high-quality studies are needed to validate these findings.

1. INTRODUCTION

Subthreshold depression (SD) is a condition defined by the presence of 2 to 4 of the nine core symptoms of depression lasting for at least two weeks. It has a significant impact on social functioning^1-4 and is considered a preclinical stage of major depressive disorder (MDD).⁵ The prevalence of SD ranges from 7.3% to 23.1%, and individuals with SD have a significantly higher risk of progressing to full-syndrome depression compared to healthy individuals.^1,6 This progression not only reduces quality of life⁷ but also imposes substantial medical and economic burdens,^8,9 along with an increased risk of mortality.¹⁰

According to a Meta-analysis, psychotherapies such as problem-solving therapy (PST), behavioral activation therapy (BAT), and cognitive behavioral therapy (CBT) may be effective options for treating SD.¹¹ However, in clinical practice, the shortage of qualified therapists often leads to long waiting times and high treatment costs, discouraging patient participation.¹² Group psychotherapy enables individuals with SD to reflect, explore, and accept themselves through structured interactions within a group setting. By creating a supportive environment and organizing targeted group activities, this therapy addresses both external and internal challenges faced by participants.¹³ Previous studies have shown that group psychotherapy is a cost-effective intervention, with comparable outcomes to individual therapy.¹⁴ Although it significantly reduces depressive symptoms in adults with SD, its effects may diminish over time.^12,15

Traditional Chinese Medicine (TCM) offers several advantages, including a holistic adjustment regulation, minimal side effects, and long-term efficacy. Although some studies have examined the use of TCM for SD, many have been limited by small sample sizes and methodological limitations.¹⁶ Five-tone therapy, based on the five-element theory, utilizes the musical tones Jue, Zhi, Gong, Shang, and Yu to regulate five viscera, emotions, and disease processes.¹⁷ When combined with psychological counseling, Jue tune music therapy has been shown to improve sleep quality, reduce anxiety and depression, and alleviate psychotic symptoms in patients with chronic insomnia and depression.¹⁸

Additional research has demonstrated that combining Jue tune music with Chinese herbs and acupuncture can significantly improve post-stroke depression.¹⁹ Our previous cohort study also showed that integrating five-element music and Baduanjin with oral sertraline in patients with mild to moderate depression led to greater reductions in HAMD scores compared to sertraline alone.²⁰ Building on prior research, clinical experience, literature reviews, and expert consultation, we developed the Yuleyin oral formula (郁乐饮) using ingredients that are both medicinal and edible. Components such as Suanzaoren (Semen Ziziphi Spinosae), Zisuye (Folium Perillae Argutae), Baihe (Bulbus Lilii Lancifolii), and Meiguihua (Flos Rosae Rugosae) help regulate qi, relieve emotional tension, and alleviate depressive symptoms. However, the lack of large-scale, multicenter randomized controlled trials and methodological limitations in existing studies have hindered conclusive assessments of the efficacy of TCM psychosomatic integration therapy for SD.

In this study, patients with SD were treated using a combination of Jue tune music, Yuleyin oral formula, and group psychotherapy. By addressing current research gaps, the study aims to provide new evidence for effective interventions in the management of SD.

2. METHODS

2.1. Study design

A multicenter randomized trial was conducted across eight TCM medical centers in China. After baseline assessments, participants were randomized into two groups. The intervention group received group psychotherapy, Jue tune music therapy, and Yuleyin oral formula. The control group received only group psychotherapy. A placebo was not used in the trial, as the manufacturing process could not replicate the taste, aroma, and appearance of Yuleyin granules (郁乐饮颗粒). The minimum required sample size was calculated based on outcome indicators for SD. Based on prior clinical data and the observed preference of patients with SD for the integrated TCM intervention, a total sample size of at least 480 participants, with a 3∶1 allocation ratio between the intervention and control groups, was determined in accordance with Phase Ⅲ clinical trial requirements outlined in the Drug Registration Administration guidelines²¹ and adjusted to reflect real-world clinical practice. Randomization was performed using a computer-generated sequence managed by an independent statistician. The study protocol was approved by the Ethics Committee of the Beijing University of Chinese Medicine (No. 2020BZYLL0605) and all participants provided informed consent. Trial registration number: ChiCTR2000032005.

2.2. Inclusion and exclusion criteria

Participants were recruited by the principal investigators using a combination of strategies, including online outreach and posted advertisements in hospitals and clinics. Inclusion criteria for SD patients were as follows: (a) age 18 years or older; (b) diagnosis of SD, defined as 2 to 4 of the nine core depressive symptoms lasting at least two weeks. Exclusion criteria included: (a) meeting DSM-5 criteria for major depression; (b) recent evidence of self-harm, current suicidal ideation or behavior, or significant cognitive impairment; (c) bipolar disorder or psychotic disorders; (d) enrollment in other clinical studies; (e) known history of substance abuse, including alcohol and drugs; (f) severe organic diseases, severe liver or renal impairment, severe arrhythmia, or cardiac insufficiency; (g) pregnant, lactating, or planning to become pregnant.

2.3. Intervention method

2.3.1. Control group

Participants received group psychotherapy once per week (supplementary Table 1). The therapy focused on SD management through group discussion, guided presentations, and case analysis, incorporating techniques such as cognitive restructuring, emotional regulation, and relaxation training.

2.3.2. Experimental group

Participants received the same group psychotherapy as the control group, along with the following two additional interventions:

2.3.2.1. Jue tune music therapy

(a) Daily 15-min sessions.

(b) The music content includes several traditional Chinese Jue tone, such as “Spring Breeze Triumphant,” “Hujia Eighteen Beats,” “Liezi Imperial Wind,” “Zhuangzhou Dreaming of Being a Butterfly,” “Jiangnan Good,” and “Neshang Qu.” These compositions aim to harmonize the five visceral organs, regulate Qi and blood circulation, and promote both physical and mental well-being.

(c) Participants used a mobile phone application to play the music, with compliance recorded in an attendance sheet.

2.3.2.2. Yuleyin oral formula

(a) Two packets of granules per dose, taken orally twice daily — once in the morning and once in the evening — for a total of 12 weeks.

(b) The formula consists of medicinal and edible components tailored to treat “visceral insufficiency” and “Qi disorder” in SD. Ingredients include: Zisuye (Folium Perillae Argutae) 9 g, Baihe (Bulbus Lilii Lancifolii) 20 g, Meiguihua (Flos Rosae Rugosae) 10 g, Gancao (Radix Glycyrrhizae) 10 g, Xiaomai (Fructus Tritici Levis) 20 g, Dazao (Fructus Jujubae) 10 g, Zhizi (Fructus Gardeniae) 10 g, Dandouchi (Semen Sojae Praeparatum) 6 g, Suanzaoren (Semen Ziziphi Spinosae) 15 g, Foshou (Fructus Citri Sarcodactylis) 10 g, and Maiya (Fructus Hordei Germinatus) 15 g. The granules were manufactured by Jiangxi Poly Company using decoction, extraction, and seasoning processes. A non-caloric sweetener was used, and all excipients met national food safety standards (GB2760-2011).

(c) Granules were dissolved in warm water and consumed, with intake completion recorded in an attendance sheet.

Both groups received treatment for 12 weeks, followed by a 12-week observational follow-up to evaluate the sustainability of outcomes.

2.4. Randomization

Randomization was performed using the TCM Intelligent Health Intervention Management Technology Platform. Patients entered their basic information via a mobile web interface and were assessed by physicians. Based on the results of a preceding pilot study, participants who met the inclusion criteria and provided informed consent were randomized by the backend system in a 3∶1 ratio to either the experimental or control group.

2.5. Outcomes

The primary outcome was the Center for Epidemiologic Studies Depression Scale (CES-D) score at week 12. The CES-D is a self-rated scale used to assess depressive symptoms, with higher scores indicating more severe depression. Secondary outcomes included dropout rate; CES-D scores at weeks 4, 8, 16, 20, and 24; and scores on the Hamilton Depression Rating Scale (HAMD-17) and the Hamilton Anxiety Scale (HAMA). The dropout rate served as an indicator of trial management and the feasibility of the study protocol. The HAMD is a clinician-rated measure of depression severity, and the HAMA is a clinician-rated measure of anxiety severity, with higher scores on both scales indicating greater symptom severity.

Safety assessments were conducted before, during, and after the intervention period. These included routine blood and urine tests, liver and kidney function tests, electrocardiograms (ECGs), and the Treatment Emergent Symptom Scale (TESS) to monitor adverse events. At week 12, all participants underwent an adverse event evaluation and safety assessments. If abnormal laboratory findings were detected, tests were repeated promptly, and a comprehensive evaluation of the participant’s medical history and current health condition was performed to assess any potential relationship to the intervention.

2.6. Data management and quality assurance

Data were managed through the TCM Intelligent Information Management Platform developed by the project team. To ensure data accuracy and authenticity, follow-up data were cross-verified regularly by at least two researchers. After data collection was completed, the dataset was exported and reviewed by independent statistical analysts. All cases were retained for final analysis based on predefined inclusion, exclusion, and elimination criteria.

2.7. Statistical analysis

A dedicated Excel database was created for data entry. Statistical analysis was performed using R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria) and IBM SPSS Statistics 26.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were used to summarize demographic and baseline information. For comparisons of continuous clinical data among multiple groups, one-way analysis of variance (ANOVA) was used. For pairwise comparisons, independent-sample t-tests or non-parametric tests were applied as appropriate. Results were reported as mean ± standard deviation ($ \bar{x} \pm s$). Categorical variables were analyzed using chi-square tests. Generalized estimating equations (GEE) were applied for the analysis of repeated measurements, and trends in outcomes over time were visualized using repeated measures ANOVA plots. Subgroup analyses were conducted using cluster analysis and multivariate logistic regression modules in SPSS.

All analyses followed the intention-to-treat principle, and missing data were imputed using the Expectation-Maximization algorithm.

3. RESULTS

3.1. Study flow and characteristics of patients

From January to July 2021, a rigorous eligibility screening was conducted. Participants were then randomized into either the control group (n = 133) or the experimental group (n = 372). Nine participants (five from the experimental group and four from the control group) were excluded due to non-compliance or loss to follow-up. A total of 496 participants were included in the final analysis [77% female; (38 ± 16) years; 367 in the experimental group; 129 in the control group]. The study design and participant flow are illustrated in Figure 1.

Figure 1. Study flowchart.

TCM: Traditional Chinese Medicine; HAMA: hamilton anxiety scale; HAMD: hamilton depression scale; CES-D: center for epidemiologic studies depression scale; CDC: complete blood cell count, URT: urine routine test, ECG: electrocardiograph; TESS: treatment emergent symptom scale.

Comparisons between the two groups showed no statistically significant differences in baseline characteristics, including age, sex, body mass index (BMI), occupation, education level, marital status, smoking history, alcohol consumption, or physical activity (P > 0.05), confirming baseline equivalence (Table 1).

Table 1.

Baseline characteristics

Characteristics	Experimental group (n = 367)	Control group (n = 129)
Age (years)	39.2±16.5	36.3±14.7
Female [n (%)]	289 (78.7)	93 (72.1)
BMI (kg/m2)	23.8±6.2	24.6±7.2
CES-D	27.4±7.7	27.6±7.5
HAMD	11.3±2.9	10.9±3.0
HAMA	14.2±6.7	13.7±6.2
Without occupation [n (%)]	5 (1.4)	1 (0.8)
Education background [n (%)]
Master's degree or higher education	68 (18.5)	30 (23.3)
Bachelor's degree	142 (38.7)	45 (34.9)
Below high school diploma	157 (42.8)	54 (41.8)
Unmarried [n (%)]	155 (42.2)	61 (47.3)
Have smoking habits [n (%)]	27 (7.4)	12 (9.3)
Alcohol consumption patterns [n (%)]
No drink	305 (83.1)	109 (84.5)
Have a drinking habit	47 (12.8)	12 (9.3)
Used to have, but have quit now	15 (4.1)	8 (6.2)
Exercise Routines [n (%)]
Almost never exercise	113 (30.8)	31 (24.0)
Occasionally exercise	159 (43.3)	58 (45.0)
Regularly exercise	95 (25.9)	40 (31.0)

Notes: control group: participants received group psychotherapy once weekly; experimental group: in addition to once-weekly group psychotherapy, participants received a 15-min session of Jue-tune music therapy daily and Yuleyin oral formula twice daily. BMI: body weight index; HAMA: hamilton anxiety scale; HAMD: hamilton depression scale; CES-D: center for epidemiologic studies depression scale. Data are presented as mean ± standard deviation for continuous variables and as number (percentage) for categorical variables. Continuous variables were analyzed by t-test or non-parametric tests, and categorical variables by χ ² test.

3.2. Primary outcome

After 12 weeks of intervention, CES-D scores significantly decreased in both groups. However, no statistically significant difference was observed between the two groups, indicating that both group psychotherapy and the TCM psychosomatic integration therapy effectively alleviated depressive symptoms in patients with SD (Table 2).

Table 2.

Analysis of the difference in CES-D scores compared to screening

Item		Experimental group (n = 367)	Control group (n = 129)	Mean difference (95% CI)	Wald χ2 value	P value
Screening		27±8	28±8
Invention	Week 4	24±8	24±8	-0.01 (-1.57, 1.55)	0	0.99
	Week 8	22±8	22±8	0.09 (-1.47, 1.65)	0.012	0.91
	Week 12	20±7	20±8	-0.13 (-1.68, 1.43)	0.025	0.87
Follow-up	Week 16	20±8	21±8	-0.85 (-2.41, 0.71)	1.144	0.29
	Week 20	20±8	20±8	-0.50 (-2.06, 1.06)	0.396	0.53
	Week 24	19±8	20±9	-0.92 (-2.48, 0.64)	1.341	0.25
Time effect	Wald χ2 value	898.14	275.91
	P value	<0.0001	<0.0001

Notes: control group: participants received group psychotherapy once weekly; experimental group: in addition to once-weekly group psychotherapy, participants received a 15-min session of Jue-tune music therapy daily and Yuleyin oral formula twice daily. CES-D: center for epidemiologic studies depression scale. Data are presented as mean ± standard deviation. Repeated measures data were analyzed using generalized estimating equations.

3.3. Secondary outcomes

Participants completed the CES-D assessment every 4 weeks over a 24-week period. GEE analysis based on the matrix model and structural assignments revealed an interaction effect of F = 4.191, P = 0.651 (> 0.05), indicating no statistically significant interaction. As a result, the analysis focused on the individual effects of intervention and time. The intervention effect showed F = 0.312, P = 0.576 (> 0.05), indicating no significant difference between the groups. In contrast, the time effect was statistically significant (F = 1172.548, P < 0.0001), indicating that CES-D scores changed significantly over time, regardless of the intervention type. Although no statistically significant differences were found between the experimental and control groups at any individual time point, the experimental group exhibited a greater downward trend in CES-D scores than the control group. Regarding the time effect, both groups showed significant reductions in CES-D scores at weeks 4, 8, and 12 during the intervention phase and at weeks 16, 20, and 24 during the follow-up phase (experimental group: F = 898.14, P < 0.0001; control group: F = 275.91, P < 0.0001). Further analysis of CES-D scores during the follow-up phase showed that the experimental group had statistically significant reductions at weeks 16, 20, and 24 compared to week 12 (F = 26.43, P < 0.0001). In contrast, the control group showed no significant change during the same period (F = 6.39, P = 0.094 > 0.05). Intra-group analysis of time effects during the follow-up period indicated a notable rebound in CES-D scores in the control group, suggesting a decline in the maintenance of treatment effects. In contrast, the experimental group maintained its improvement (Tables 2 and 3).

Table 3.

Analysis of the difference in CES-D scores compared to week 12

Time	Experimental group (n = 367)			Control group (n = 129)
	Mean Difference (95% CI)	Wald χ2 value	P value	Mean Difference (95% CI)	Wald χ 2 value	P value
Week 16	0.02 (-0.48, 0.51)	0.01	0.944	0.74 (-0.10, 1.59)	2.958	0.085
Week 20	-0.29 (-0.78, 0.21)	1.27	0.259	0.09 (-0.76, 0.93)	0.043	0.837
Week 24	-1.11 (-1.61, -0.62)	19.4	<0.0001	-0.32 (-1.16, 0.53)	0.545	0.46
Time effect		26.43	<0.0001		6.39	0.094

Notes: control group: participants received group psychotherapy once weekly; experimental group: in addition to once-weekly group psychotherapy, participants received a 15-min session of Jue-tune music therapy daily and Yuleyin oral formula twice daily. CES-D: center for epidemiologic studies depression scale; CI: confidence interval. Data are presented as mean difference (95% confidence interval). Repeated measures data were analyzed using generalized estimating equations.

As noted above, the number of dropouts was 5 in the experimental group and 4 in the control group, corresponding to dropout rates of 5/372 (1.34%) and 4/133 (3.00%), respectively. Both groups showed low clinical dropout rates and high levels of participation and compliance, indicating the feasibility of the study protocol.

Intra-group analysis showed a significant reduction in Hamilton Depression Rating Scale (HAMD) scores in the experimental group after the intervention (Z = -13.694, P < 0.0001). The control group also showed a significant reduction in HAMD scores (Z = -7.695, P < 0.0001). However, inter-group analysis revealed no significant difference in HAMD scores between the two groups after the intervention (Z = -0.577, P = 0.564 > 0.05) (Table 4). Intra-group analysis of Hamilton Anxiety Scale (HAMA) scores showed a significant decrease in the experimental group after the intervention (Z = -11.223, P < 0.0001), and the control group also demonstrated a significant reduction (Z = -6.408, P < 0.0001). Inter-group analysis showed no significant difference between the two groups after the intervention (Z = -1.161, P = 0.246 > 0.05) (Table 4).

Table 4.

Analysis of differences in HAMD and HAMA scores

Items		Experimental group (n = 367)	Control group (n = 129)
HAMD	screening	11±3	11±3
	week 12	8±4a	7±4b
HAMA	screening	14±7	14±6
	week 12	10±6a	9±7b

Notes: control group: participants received group psychotherapy once weekly; experimental group: in addition to once-weekly group psychotherapy, participants received a 15-min session of Jue-tune music therapy daily and Yuleyin oral formula twice daily. HAMD: hamilton depression scale; HAMA: hamilton anxiety scale. Data are expressed as mean ± standard deviation. Intragroup comparisons (Week 12 vs screening) were performed separately for the control group and the experimental group using the t-test or non-parametric tests. ^aP < 0.0001, compared with screening in the experimental group; ^bP < 0.0001, compared with screening in the control group.

3.4. Safety analysis

Only the experimental group received Yuleyin oral formula, a medicinal and edible preparation. The observed adverse reactions included the following: one patient developed oral ulcers and dry mouth after 10 weeks of use, which resolved after discontinuation; one patient experienced stomach pain and another vomited once during the second week, with both symptoms subsiding after continued use. Regarding safety indicators, two participants in the control group showed elevated creatinine levels. In the experimental group, one participant had a slight increase in creatinine, while four had mildly elevated alanine aminotransferase and aspartate aminotransferase levels. These changes may have been related to other medications taken for unrelated conditions. No severe liver or kidney dysfunction was observed during follow-up. All other participants showed no significant abnormalities in routine blood and urine tests or liver and kidney function tests.

4. DISCUSSION

At present, global interventions for SD remain exploratory. Emerging evidence increasingly supports psychotherapy, which has shown efficacy comparable to antidepressants and other treatments.¹¹ This was consistent with outcomes in our control group. After 12 weeks, both the TCM psychosomatic integration therapy-which included group psychotherapy, Jue tone music therapy, and Yuleyin oral formula-and group psychotherapy alone demonstrated clinical efficacy in reducing depressive symptoms, improving self-assessed physical health, and lowering anxiety, with low dropout rates and few adverse events. While both approaches were effective, no statistically significant differences were found between them. From a health economics perspective, this suggests that psychotherapy alone may be sufficient during the intervention phase. A notable finding was that, unlike the control group, the experimental group showed a continued decrease in CES-D scores through week 24 during the follow-up period. This may indicate the potential long-term benefits of a TCM psychosomatic integration therapy for individuals with SD.

In individuals with SD, psychological interventions such as group and individual psychotherapy were associated with a significant reduction in the incidence of MDD at post-treatment assessment, according to a Meta-analysis.²² Given similar outcomes to individual psychotherapy and better cost-effectiveness, Rosendahl et al. recommended wider use of and specialized training in group therapy based on strong supporting evidence.²³ Group psychotherapy is a promising treatment that has been shown in previous studies to effectively relieve SD.^12,15 SD also responds well to group psychotherapy guided by TCM philosophy. Tan et al. found that patients with SD benefited from TCM group psychotherapy, which focuses on encouraging Yang to suppress Yin, as reflected in CES-D scores.¹³ Jin noted that the "bio-psycho-social" medical model of modern medicine is highly compatible with TCM group psychotherapy.²⁴ According to Zhang et al,²⁵ SD patients can develop positive emotions, enhance psychological resilience, and adopt a more optimistic outlook by participating in group counseling activities such as group training, dialectical emotion training, realistic problem-solving training, and group farewell sessions.

Group psychotherapy for patients with SD has been shown in a Meta-analysis to significantly reduce depressive symptoms in post-treatment populations, including older adults and working individuals; however, the effect was not sustained once the intervention ended.¹⁵ The rebound in symptoms observed at week 16 in the control group of this study may be related to the stress caused by losing group support. The therapy followed a rolling format in which participants exited the group upon completing their sessions, with limited attention given to emotional separation. Yalom et al ²⁶ emphasized that the end of therapy should be clearly defined, as boundary issues and the limitations of treatment become more prominent afterward. Traditional group therapy often addresses separation by exchanging blessings or small gifts and by discussing separation during the final sessions. However, the open-ended, online format used in this study made it difficult to apply these traditional methods. Participants maintained regular contact with researchers during the intervention, which served as a form of social support. This support diminished after the intervention ended, which may have contributed to the reduced sustainability of treatment effects, as reflected in the follow-up results.

SD is classified as an emotional disorder in Chinese medicine. TCM provides multiple treatment options, including five-tone therapy, herbal medicine, acupuncture, and qigong exercises. Studies have shown that music may improve mood through several mechanisms, such as modulation of the autonomic nervous system (e.g., heart rate variability),²⁷ regulation of neural activity in multiple brain circuits, and enhancement of motor and cognitive functions.²⁸ Based on the core principles of TCM, the five-tone theory integrates acoustic medicine with both music theory and clinical practice, especially in psychological care. This approach reflects a novel integration of life science and humanistic values.²⁹ Gu et al ³⁰ reported that five-tone therapy is more effective than medication alone in treating SD. It relieves depressive symptoms, reduces the risk of adverse effects, and improves brain MRI features in patients.³⁰ Liu et al³¹ also found that combining five-tone therapy with conventional treatment rapidly alleviated emotional symptoms in patients with post-stroke SD, while modulating amino acid neurotransmission, promoting neurological recovery, and lowering the risk of recurrent depressive episodes. Dong et al ³² suggested that five-tone therapy enhances physiological function through multiple mechanisms, including acoustic resonance, stimulation of neuroplasticity, and regulation of neuroendocrine pathways, inflammatory mediators, and monoamine neurotransmitters.

Among the five tones, the Jue tone is characterized by a high, sustained pitch. Jue tone music can influence the movement and circulation of qi, which may help calm the mind, relieve sadness, and improve sleep.³³ Jue tone therapy has been shown to improve sleep and quality of life in patients with insomnia and depression, and may reduce anxiety and depressive symptoms.³⁴ It has also been found effective in relieving depression, anxiety, and other main symptoms in patients with premenstrual syndrome.³⁵ Patients with chronic insomnia and depression may benefit from Jue tone music therapy as an adjunct to psychological treatment, leading to improved quality of life and reduced symptoms of anxiety and depression.¹⁸

Yuleyin is a medicinal and edible decoction developed through extensive clinical practice, based on the theory of TCM constitution and fundamental principles. It is a clinically optimized combination of two classical formulas: Ganmai Dazao decoction (甘麦大枣汤) and Zhizi Chi decoction (栀子豉汤), with adjustments made to the ingredients. Ganmai Dazao decoction is a traditional formula known to nourish the heart, calm the mind, and harmonize the middle to relieve restlessness. Guo et al ³⁶ reported that this formula improved depression-like symptoms and increased hippocampal monoamine levels in depressed rodents, possibly by modulating synaptic proteins and exerting neuroprotective effects. Zhizi Chi decoction is used to clear heat and relieve irritability by dispersing constrained internal heat. Studies have shown that its antidepressant effects are related to neuroprotection; the combination of Zhizi (Fructus Gardeniae) and Dandouchi (Semen Sojae Praeparatum) improved PC12 cell viability, increased glutathione reductase and superoxide dismutase activity, and reduced lactate dehydrogenase levels, cell apoptosis, and reactive oxygen species.³⁷ According to TCM theory, Baihe (Bulbus Lilii Lancifolii) clears the heart and calms the mind, while Meiguihua (Flos Rosae Rugosae) helps to release constrained liver-qi. These herbs may serve as adjunct therapies for improving depressive symptoms. Scientific studies have shown that Baihe (Bulbus Lilii Lancifolii) has neuroprotective effects against corticosterone-induced PC12 cell damage, with antidepressant activity possibly mediated by its polysaccharide components.³⁸ Meiguihua (Flos Rosae Rugosae) was found to increase serum serotonin levels and reduce depression-like behaviors in a chronic unpredictable mild stress (CUMS) mouse model.³⁹ Suanzaoren (Semen Ziziphi Spinosae) is used to nourish the heart and liver, calm the mind, and stabilize the spirit. Cheng et al. reported that its extract improved CUMS-induced sleep and behavioral disturbances in mice, potentially through coordinated modulation of 5-hydroxytryptamine (5-HT)/hypothalamic-pituitary-adrenal (HPA) axis pathways, hippocampal protection, enhanced synaptic plasticity, restoration of the blood-brain barrier, and anti-inflammatory and antioxidant effects.⁴⁰ Zisuye (Folium Perillae Argutae) promotes the release of external pathogens and disperses cold, while regulating qi and harmonizing the stomach. To date, 271 natural compounds have been identified in Zisuye (Folium Perillae Argutae), including phenolic acids, flavonoids, and essential oils, which exhibit antioxidant, antimicrobial, anti-inflammatory, and neuroprotective properties.⁴¹ Zisuye (Folium Perillae Argutae) administration has shown significant antidepressant-like effects in CUMS-induced depressed mice, possibly through serotonergic modulation and anti-inflammatory mechanisms.⁴² Maiya (Fructus Hordei Germinatus) helps move qi, resolve food stagnation, and strengthen the spleen to improve appetite. Dietary supplementation with malt and polymalt extracts significantly reduced depressive-like behaviors in animal models.⁴³ Fermented wheat germ has also been reported to have antidepressant effects, likely through restoration of the disrupted brain-gut axis.⁴⁴ The medicinal effects of Foshou (Fructus Citri Sarcodactylis) include regulating liver Qi, relieving stomachache, and resolving dampness-phlegm, according to TCM theory. Network pharmacology analysis identified six key components in Foshou (Fructus Citri Sarcodactylis) (7-hydroxycoumarin, isoscopoletin, diosmin, hesperidin, 5,7-dimethoxycoumarin, and bergapten), which may contribute to its therapeutic effects against depression, chronic gastritis, dyspepsia, and peptic ulcer. ⁴⁵Gancao (Radix Glycyrrhizae) is traditionally used to strengthen the spleen, replenish Qi, clear heat, remove toxins, and harmonize other herbs. Its main active components, total flavonoids and liquiritin, have antidepressant effects by regulating the HPA axis, increasing monoamine neurotransmitter levels, and exerting anti-inflammatory, anti-apoptotic, and antioxidant effects.⁴⁶ These components may work synergistically with group psychotherapy to enhance neuroplasticity and reduce inflammation related to depression,⁴⁷ consistent with the TCM principle of integrating physiological and psychological regulation.

Following expert discussions, Yuleyin was integrated with Jue tone music therapy and group psychotherapy into a comprehensive intervention program. Subsequent validation confirmed its safety and effectiveness in alleviating SD. The continued improvement seen in the experimental group may reflect TCM’s holistic focus on “cultivating vitality” and promoting “self-healing”. While group psychotherapy alone provided temporary social support, the integrated approach may have enhanced resilience through multiple pathways: (a) neuroendocrine regulation by music therapy, (b) biochemical support for neurotransmitter balance from Yuleyin, and (c) cognitive restructuring from psychotherapy. This model aligns with the psychoneuroimmunology framework, in which mind-body interventions reduce allostatic load by integrating behavioral, neurological, and immune system responses.⁴⁸

Previous studies in TCM psychosomatic medicine have been limited by small sample sizes and a lack of focus on SD. As the first multicenter randomized controlled trial to apply TCM psychosomatic integration therapy to SD, this study addressed these gaps through a rigorous design, including a large sample size, randomization, and comprehensive safety monitoring. Validated tools such as CES-D, HAMD-17, and HAMA were used to ensure reliable outcome assessment. The results show that TCM psychosomatic integration therapy targeting both physiological and psychological domains (i.e., group psychotherapy, Jue tone music therapy, and Yuleyin oral formula) may be more effective than psychological therapy alone in improving physical vitality and supporting long-term recovery. This may be due to synergistic effects between TCM’s holistic philosophy and modern psychosomatic mechanisms. For example, CES-D scores in the experimental group continued to decline during follow-up, while the control group experienced a rebound. This suggests that multimodal TCM interventions may enhance resilience by modulating neuroendocrine function, balancing neurotransmitters, and supporting cognitive restructuring. However, the study has limitations, including potential bias from self-reported data, limited generalizability due to recruitment from only five Chinese cities, and shortened follow-up periods due to the COVID-19 pandemic. These factors warrant further investigation to confirm long-term effectiveness.

In conclusion, The TCM intervention program — based on psychosomatic therapy and delivered online—combining group psychotherapy with Jue tone music therapy and Yuleyin oral formula, may improve outcomes in patients with SD. It demonstrated good safety and feasibility, and superior long-term effectiveness compared to basic group psychotherapy. Future studies should prioritize the identification and validation of mechanistic biomarkers (e.g., heart rate variability, inflammatory cytokines) to substantiate these neuro-psycho-immunological pathways.

Funding Statement

Supported by Sanming Project of Medicine in Shenzhen (No. SZZYSM202105010); National Key Research and Development Program Project Fund: Clinical Evaluation of Interventions for Subthreshold Depression, Insomnia, and Mild Cognitive Impairment (No. 2019YFC1710103)