Clinical efficacy of Sihai Shuyu Pill-Euthyrox for thyroid nodules and real-world research on patients’ anxiety/depression

Abstract

BACKGROUND

Patients with thyroid nodules (TNs) commonly experience emotional issues, such as anxiety and depression, which impact their quality of life and may adversely affect their treatment outcomes.

AIM

To evaluate the effectiveness of Sihai Shuyu Pill combined with Euthyrox for TNs and its impact on patients’ mental health using real-world data and a retrospective cohort design.

METHODS

This study included 120 patients diagnosed with TNs in the Sichuan Provincial People’s Hospital between June and December 2024. They were divided into observation and control groups (n = 60 each) according to treatment. The former received Sihai Shuyu Pill-Euthyrox, whereas the latter received only Euthyrox for 3 months. The thyroid function indexes [thyroid stimulating hormone (TSH), free triiodothyronine, and free thyroxine], TN size alterations, and anxiety and depression were detected and evaluated pre- and post-treatment in both groups.

RESULTS

The experimental group (98.33%) had a higher total effective rate than the control group (91.67%) (P < 0.05). After treatment, the TN volume, nodule counts, and largest nodule diameter were reduced in both groups (P < 0.05), with the experimental group showing more obvious improvement. TSH, free triiodothyronine, and free thyroxine levels were reduced in both groups after treatment (P < 0.05), with the experimental group having lower TSH than the control group (P < 0.05). The patient anxiety and depression scores in both groups were reduced after treatment (P < 0.05), with the experimental group exhibiting more significant improvement. The experimental group showed a lower adverse reaction incidence than the control group, although not statistically significant (P > 0.05).

CONCLUSION

The combined treatment plan of traditional Chinese and Western medicine has a synergistic advantage in improving nodular symptoms, regulating thyroid function, and alleviating negative emotions, providing evidence-based support for TN treatment.

Key Words: Sihai Shuyu Pill; Euthyrox; Thyroid nodules; Combining treatment; Anxiety; Depression; Real-world research

Core Tip: Thyroid nodules (TNs) represent a common thyroid disorder with incompletely understood pathogenesis. Patients with TNs commonly experience emotional issues, such as anxiety and depression, which can impact their quality of life and may adversely affect their treatment outcomes. In recent years, increasing research has focused on the efficacy of integrated Chinese and Western medicine approaches for TN treatment. Sihai Shuyu Pill is a traditional Chinese herbal formula comprising seaweed, kelp, clam shells, wood fragrant, dried tangerine peel, and other herbs. This formulation functions to nourish the liver, regulate qi, resolve phlegm, and disperse nodules. It is commonly used in traditional Chinese medicine to treat thyroid enlargement and TN caused by liver qi stagnation. This study aims to investigate the effectiveness of Sihai Shuyu Pill-combined Euthyrox for TNs and its effects on mental health.

INTRODUCTION

Thyroid nodules (TNs) are a common thyroid disorder, with an incidence rate of approximately 3%-15%, and they gradually increase with age, especially among women[1,2]. TN pathogenesis is complex and thus remains incompletely understood. TN occurrence is associated with various factors such as genetics, environment, diet, and lifestyle[3]. In addition, long-term mental stress, endocrine disorders, and other factors may increase TN development risk[4]. People should consider these potential risk factors and maintain a healthy lifestyle, such as a balanced diet, moderate exercise, and a good state of mind, to reduce TN risk. For high-risk groups, regular thyroid examinations should be conducted for early detection and treatment[1,3]. Moreover, patients with TNs often have abnormal thyroid function, such as excessive or insufficient secretion of thyroid hormones, which may adversely affect their condition[5].

Follow-up observations showed that 10%-15% of patients may develop thyroid cancer after diagnosis[6]. Deteriorated TNs often require surgery or ablation, with postoperative complications, high recurrence risk, and long-term - sometimes lifelong - medication needs. These factors impose substantial psychological burdens and negative emotions on patients. Meanwhile, anxiety, depression, and other emotional problems are also common among patients with TNs; the mechanism of their occurrence may be related to factors such as abnormal secretion of thyroid hormones and patients’ concerns about the disease[7]. These emotional problems affect patients’ quality of life and likely adversely affect their treatment. Negative emotions contribute to TN development and may worsen prognosis. Therefore, TN management warrants attention to patients’ mental health and targeted interventions. Current clinical treatment methods for TNs mainly include surgical and drug treatments. However, surgical treatment carries certain risks and complications and is unsuitable for all patients. Drug therapy remains routine, with levothyroxine commonly used to suppress thyroid-stimulating hormones and limit TN growth[8]. However, levothyroxine monotherapy shows limited efficacy in some patients, and long-term use may cause adverse reactions such as arrhythmia and osteoporosis[8]. According to traditional Chinese medicine (TCM), TN occurrence is related to factors such as liver depression, qi stagnation, and phlegm-dampness stagnation. Sihai Shuyu Pill (SSP), a TCM formula capable of soothing the liver, regulating qi, resolving phlegm, and dispersing nodules, has some potential for TN treatment[9,10]. Accumulating studies are now exploring the efficacy of integrating TCM with Western medicine in TN treatment. SSP comprises seaweed, kelp, sea clam shell, wood incense, dried tangerine peel, and other herbs. It is commonly used in TCM to treat diseases such as goiters and scrofula caused by liver depression and qi and phlegm-dampness stagnation[11]. SSP medicinal components have immune-regulating, antitumor, and anti-inflammatory effects, which may benefit TN treatment[12]. Building on this background, this study evaluated the feasibility and effectiveness of TCM-integrated Western therapy for TNs by assessing SSP-levothyroxine treatment outcomes and pre-post changes in patient anxiety and depression.

MATERIALS AND METHODS

Research subjects

This study included 120 patients diagnosed with benign TNs at the Endocrinology Department, Thyroid Surgery Department, TCM Department, and Physical Examination Center of our hospital from June 2024 to December 2024. These subjects, having met the inclusion criteria, were divided into control and observation groups (n = 60 each) based on the treatment approach. The control group had 34 male and 26 female patients aged 20-69 years (mean age: 44.21 ± 3.52 years; disease duration: 2.95 ± 1.30 years). The experimental group had 36 and 24 male and female patients aged 21-66 years (mean age: 43.85 ± 3.17 years; disease duration: 3.05 ± 1.37 years). Baseline characteristics did not differ significantly between the two groups (P > 0.05).

Inclusion criteria: Age between 18 years and 70 years; ultrasonically confirmed benign TNs.

Exclusion criteria: Patients with severe heart, liver, kidney, and other organ dysfunction; patients allergic to SSP or levothyroxine; patients with mental illness or cognitive impairment who could not cooperate with treatment or assessment; pregnant or breastfeeding women; patients who have used other medications that may affect thyroid function or mood within one month before enrollment; allergic constitution; patients with TNs suspected of malignant transformation or confirmed thyroid cancer.

Treatment methods

Control group treatment: Levothyroxine Sodium Tablets (Euthyrox^®) alone, once daily, adjusted according to individual thyroid function.

Observation group treatment: SSPs (Beijing Tong Ren Tang, National Drug, approval No. Z11021111) were added to the control group. Medicinal ingredients: Qingmu Xiang 15 g, dried tangerine peel 9 g, sea egg case 60 g, Kelp 60 g, seaweed 60 g, sea clam powder 9 g. Soak in boiling water to remove salt, grind together into a fine powder, make pills the size of paulownia seeds, 9 g each time, take with warm water, three times a day.

Both groups were treated for 12 consecutive weeks, with a follow-up visit every 4 weeks.

Observation indicators

Clinical efficacy evaluation criteria: Evaluated based on symptom improvement and TN size changes.

Clinical cure: The patient’s symptoms completely disappear, and the TN completely disappears or shrinks to an almost imperceptible extent.

Marked effect: The patient’s symptoms improve significantly, with TN size shrinking significantly.

Effective: The patient’s symptoms are alleviated, and the TN volume is reduced to a certain extent.

Ineffective: No significant improvement existed in the patient’s symptoms, and the TN volume remains largely unchanged or even increases.

TN: TN maximum diameter length is measured by ultrasound, as well as TN volume, TN counts, and nodule maximum diameter.

Thyroid function indicator detection: Indicators were assessed by measuring serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4). Fasting peripheral venous blood (3 mL) was collected, allowed to stand for 30 minutes, and centrifuged at 3000 r/minutes for 10 minutes to separate the serum. Serum TSH, FT3, and FT4 levels were then quantified using a chemiluminescence immunoassay.

Assessment methods for anxiety and depression: The Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were used to assess mental state, with a full score of 100, with lower scores reflecting a better state[10].

Adverse reactions: Adverse reaction incidence during treatment was recorded in both groups.

Statistical analysis

Using PASS15.0 (Power Analysis and Sample Size, NCSS, LLC) for calculation, the study sample size was determined based on the primary endpoint - clinical response rate. Based on historical data from the previous literature, the expected response rate for levothyroxine treatment of TN is 70%. We hypothesize that adding SSP treatment will increase the response rate to 92%. With a two-sided test level of α = 0.05 and 80% power, each group required a minimum sample size of 46 subjects, totaling 92 subjects. Accounting for a 20% loss to follow-up rate, each group required a minimum sample size of 58 subjects, totaling 116 subjects.

The statistical processing software SPSS27.0 was used for processing and analysis. The measurement data were expressed as mean ± SD in which a t-test was used. Count data were expressed as rate n (%) and tested by χ². P < 0.05 indicates a statistically significant difference.

RESULTS

Comparison of clinical efficacy between two groups

The observation group showed a significantly higher total effective rate than the control group (98.33% vs 91.67%; P < 0.05; Table 1).

Table 1 Comparison of clinical efficacy between two groups of patients, n (%).

Grouping	Healing	Take effect	Effective	Ineffective	Overall efficacy
Control group (n = 60)	4 (6.67)	23 (38.33)	28 (46.67)	5 (8.33)	55 (91.67)
Experimental group (n = 60)	8 (13.33)	36 (60.00)	15 (25.00)	1 (1.67)	59 (98.33)
χ2 value					10.793
P value					0.013

Pre- and post-treatment TN comparison in both groups

After treatment, TN volume, nodule count, and maximum nodule diameter decreased significantly in both groups (P < 0.05), with the observation group exhibiting greater reductions than the control group (Table 2).

Table 2 Comparison of thyroid nodules before and after treatment in two groups of patients, mean ± SD.

Grouping	Volume of thyroid nodules (mL)		Number of thyroid nodules (units)		Maximum nodule diameter (mm)
	Before intervention	After the intervention	Before the intervention	After the intervention	Before the intervention	After the intervention
Control group (n = 60)	14.84 ± 2.51	12.35 ± 2.23a	2.29 ± 1.02	1.87 ± 0.85a	16.98 ± 1.95	15.26 ± 1.87a
Experimental group (n = 60)	14.67 ± 2.17	9.88 ± 1.98a	2.35 ± 0.94	1.52 ± 0.76a	16.37 ± 2.15	13.55 ± 1.68a
t value	0.837	4.521	0.395	2.135	0.748	2.376
P value	0.185	0.008	0.674	0.035	0.214	0.020

^aP < 0.05 vs before the intervention.

Pre- and post-treatment comparison of thyroid function indicators between the two groups

After treatment, TSH differed significantly between groups (P < 0.05), whereas FT3 and FT4 showed no significant between-group differences (P > 0.05) (Table 3).

Table 3 Comparison of thyroid function indicators before and after treatment between the two groups of patients, mean ± SD.

Grouping	TSH (μIU/mL)		FT3 (pg/mL)		FT4 (pg/mL)
	Before intervention	After the intervention	Before the intervention	After the intervention	Before the intervention	After the intervention
Control group (n = 60)	1.95 ± 0.86	1.43 ± 0.67a	3.24 ± 1.05	2.12 ± 0.83a	0.95 ± 0.14	0.86 ± 0.14a
Experimental group (n = 60)	1.92 ± 0.95	1.07 ± 0.53a	3.18 ± 1.14	2.06 ± 0.77a	0.97 ± 0.20	0.83 ± 0.17a
t value	0.584	2.958	0.854	1.047	0.674	1.121
P value	0.445	0.034	0.181	0.076	0.411	0.069

^aP < 0.05 vs before the intervention.

TSH: Thyroid stimulating hormone; FT3: Free triiodothyronine; FT4: Free thyroxine.

Pre- and post-treatment comparison of anxiety and depression between the two groups

After treatment, SDS and SAS scores decreased significantly in both groups (P < 0.05), with the experimental group showing lower post-treatment scores than the control group (Table 4).

Table 4 Comparison of anxiety and depression before and after treatment between the two groups, mean ± SD.

Grouping	SDS		SAS
	Before intervention	After the intervention	Before the intervention	After the intervention
Control group (n = 60)	53.84 ± 5.92	49.01 ± 3.04a	53.24 ± 5.42	50.31 ± 6.77a
Experimental group (n = 60)	53.04 ± 5.94	43.93 ± 6.4a	53.98 ± 5.83	44.34 ± 4.88a
t value	0.527	3.251	0.842	3.395
P value	0.486	0.028	0.184	0.024

^aP < 0.05 vs before the intervention.

SDS: Self-Rating Depression Scale; SAS: Self-Rating Anxiety Scale.

Adverse reaction incidence

Although not statistically significant, the experimental group had a lower adverse reaction incidence than the control group (P > 0.05; Table 5).

Table 5 Comparison of incidence of adverse reactions between the two groups, n (%).

Grouping	Gastrointestinal discomfort	Allergy	Headache	Palpitations	Others	Total incidence rate
Control group (n = 60)	5 (8.33)	2 (3.33)	2 (3.33)	1 (1.67)	1 (1.67)	11 (18.33)
Experimental group (n = 60)	3 (5.00)	1 (1.67)	1 (1.67)	0	1 (1.67)	6 (10.00)
χ2 value						0.958
P value						0.215

DISCUSSION

SSP-lethyroxine efficacy in TN treatment

This study found that SSP-levothyroxine treatment achieved significantly greater efficacy in TN treatment than levothyroxine alone. The total effective rate of the experimental group was 98.33%, significantly exceeding that of the control group (91.67%; P < 0.05). These findings indicate that adding SSP to levothyroxine improves therapeutic outcomes in TN treatment, with advantages in promoting nodule regression and alleviating symptoms. The experimental group demonstrated superior improvement in nodule volume, nodule count, and maximum nodule diameter compared with the control group (P < 0.05), confirming SSP-levothyroxine efficacy in reducing nodules. SSP-levothyroxine can produce a complementary synergistic effect. SSP ingredients, such as seaweed, kelp, and sea clam shells, can soothe the liver and relieve depression, improving the state of liver qi stagnation, thereby helping alleviate TN symptoms. In addition, SSP medicinal ingredients exert phlegm-resolving, nodule-dispersing effects that may reduce TN volume[13]. Moreover, levothyroxine inhibits TSH secretion and reduces TN growth, thereby boosting its regression[14].

Effects on thyroid function indicators

After treatment, TSH, FT3, and FT4 levels decreased in both groups (P < 0.05), but the TSH level in the observation group was significantly lower than that in the control group (P < 0.05). This result suggests that SSP–levothyroxine has a more significant effect in regulating thyroid function. SSP ingredients, such as seaweed and kelp, have anti-inflammatory and immunomodulatory effects, which can improve the local inflammatory response and thereby reduce excessive thyroid hormone synthesis[15]. Levothyroxine further inhibits TSH secretion and lowers its levels by directly supplementing thyroid hormones. This dual inhibition mechanism resulted in significantly lower TSH levels in the observation group than in the control group[8]. In addition, the decline in FT3 and FT4 levels mainly resulted from the complementary effect of levothyroxine, which gradually increased thyroid hormone levels and, via a feedback mechanism, inhibited TSH secretion, thereby reducing thyroid hormone synthesis and release[10]. Although the SSP anti-inflammatory and immunomodulatory effects further reduced excessive thyroid hormone synthesis, no significant difference in FT3 and FT4 levels existed between the two groups (P > 0.05). Nevertheless, SSP-levothyroxine still showed a significant advantage in suppressing TSH secretion, thereby improving thyroid dysfunction in patients[13]. This synergistic effect not only optimizes thyroid hormone levels but also provides patients with a more comprehensive therapeutic effect.

Effects on patients’ anxiety and depression

This study found that SSP-levothyroxine effectively improved the clinical symptoms of TNs while significantly reducing anxiety and depression in patients. After treatment, the SAS and SDS scores of both groups decreased (P < 0.05), but the improvement in the observation group was more significant (P < 0.05). This suggests that SSP has a significant advantage in improving the emotional states of patients. TN, as a chronic disease, often causes persistent psychological stress and discomfort in patients, which may lead to or exacerbate anxiety and depression[13]. SSP supplementation, through its effects of soothing the liver, relieving depression, and regulating qi movement, may help relieve TN-induced psychological burden[16]. In addition, SSP marine components (e.g., seaweed and kelp) may exert anti-inflammatory effects and improve mood by modulating the neuroendocrine pathway[14]. These ingredients may reduce anxiety and depression symptoms by participating in hypothalamic-pituitary-adrenal axis regulation and lowering cortisol levels. Meanwhile, TCM herbs such as wood incense and dried tangerine peel may help improve mood problems caused by liver qi stagnation through their liver-soothing and qi-regulating properties[8]. In TCM theory, liver qi stagnation is regarded as a key pathological mechanism of anxiety and depression. Modern research suggests that oxidative stress is associated with the development of various mental disorders[7,9]. SSP antioxidant components may help protect nerve cells and improve mood by reducing free radicals’ production and oxidative stress-induced damage. However, these results remain inferential because modern pharmacological evidence directly linking SSP components such as wood incense or dried tangerine peel to mood-enhancing effects (e.g., anxiolytic or antidepressant activity) remains limited. Peer-reviewed animal studies, cellular mechanism research, and clinical trials to substantiate these claims are unavailable. Similarly, this may also provide a basis for future in vitro experimental research. Moreover, levothyroxine may indirectly improve the mental state of patients by regulating thyroid hormone levels[8]. Thyroid hormones play an important role in mood regulation, and an imbalance in hormone levels can lead to mood problems, while levothyroxine use helps maintain thyroid hormone level stability[17]. Therefore, SSP-levothyroxine therapy may act through multiple pathways, improving TN-related outcomes and more effectively alleviating anxiety and depression, thereby offering a potentially beneficial option for comprehensive TN management with clinical applicability.

Safety assessment

When evaluating safety, we found that the adverse reaction incidence was 10.00% in the observation group and 18.33% in the control group. Although the between-group difference was not significant (P > 0.05), adverse reaction disparities exceeding 10% warrant further subgroup analyses (e.g., stratified by TSH suppression intensity). The main adverse reactions in the observation group were gastrointestinal discomfort, allergy, headache, and palpitations, but the overall incidence was relatively low. This fully demonstrates the good safety of SSP-levothyroxine in TN treatment. The natural herbal ingredients contained in SSP are well tolerated. Meanwhile, the standardized dose control of levothyroxine ensures treatment safety. This combination therapy effectively improves TNs with minimal adverse reaction incidence, thus ensuring treatment safety and patient comfort[14,18].

Study limitations and future prospects

Although this study suggests that SSP-levothyroxine improves TN outcomes and psychological symptoms, several limitations remain. The small sample size and short follow-up period warrant larger, longer prospective studies to confirm these findings. In addition, this study focused mainly on short-term efficacy, and more long-term follow-up data will be needed in the future to assess long-term efficacy and safety. Despite this study’s initial exploration of SSP action mechanisms, specific pharmacological pathways require further investigation. This retrospective cohort study design provides representative real-world clinical data; however, the lack of causal inference methods (e.g., propensity score matching, inverse probability weighting, or covariate adjustment) may leave residual confounding uncontrolled. Uncorrected confounding factors may distort causal interpretations of treatment group differences. For adverse reaction disparities exceeding 10%, further subgroup analyses (e.g., stratified by TSH suppression intensity) are warranted. Consequently, comprehensive, large-scale prospective studies are needed to validate our findings.

CONCLUSION

SSP-levothyroxine utilization in TN treatment markedly improves clinical efficacy, effectively enhances thyroid function and nodule status, and reduces anxiety and depression, with good safety and application prospects. Future studies should further expand the sample size, extend the follow-up time, and extensively explore its action mechanism to provide a new approach and evidence-based validation for TN treatment.