Efficacy and mechanism of Shugan Jieyu combined with sertraline in alcohol-dependent patients with depression: A randomized clinical study

Abstract

BACKGROUND

Proper antidepressant use can improve mood and reduce desire to drink alcohol in alcohol-induced-affective-disorder patients. Shugan Jieyu capsules (SJC) have various impacts on the central nervous system, producing antidepressant effects. Traditional Chinese medicine (including Shugan Jieyu) is highly therapeutic in treating alcohol dependence, with few side-effects. However, research on its combination with Western antidepressants (e.g., sertraline) to improve patients’ depression is insufficient.

AIM

To evaluate the clinical efficacy and safety of SJC combined with sertraline vs sertraline monotherapy in alcohol-dependent patients with comorbid depression.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial. Sixty patients (aged 18-65 years) were randomly assigned to two groups (n = 30 per group). Primary outcome: Hamilton Depression Rating Scale (HAMD)-17 changes over 6 weeks. Benzodiazepines were permitted for severe insomnia.

RESULTS

The HAMD-17 score of the study (vs control) group was lower at treatment weeks 2, 4, and 6 (P < 0.05). Regarding intra-group comparisons, the study group’s HAMD score was significantly lower than that before treatment from week 2 (P < 0.05), while that of the control group was significantly lower than that before treatment from week 4 (P < 0.05). The study and control groups’ total efficacy rates were 90% and 73.3%, respectively, showing a significant difference in efficacy (χ² = 4.812, P = 0.028). No significant difference was observed in adverse reactions’ incidence between the groups at treatment weeks 2, 4, and 6 (P > 0.05).

CONCLUSION

SJC-sertraline combination therapy accelerates depressive symptom relief (by 2 weeks) and improves response rates (+16.7%) in alcohol-dependent patients, without increasing adverse events. Clinical outcomes suggest potential synergistic mechanisms, though no biomarker analyses were performed.

Key Words: Shugan Jieyu capsules; Sertraline; Alcohol dependence; Depression; Efficacy; Mechanism

Core Tip: This study investigates the efficacy and safety of combining Shugan Jieyu capsules (SJC) with sertraline in treating alcohol dependence and comorbid depression. The results show that the combination significantly reduces depression symptoms, with improved outcomes seen as early as 2 weeks. The study group demonstrated a higher total efficacy rate (90%) compared to the control group (73.3%), with no significant difference in adverse reactions between the two groups. These findings suggest that SJC, when used alongside sertraline, offer a promising, safe, and effective treatment option for patients with alcohol-induced depression.

INTRODUCTION

Patients with alcohol dependence who drink heavily over long periods can develop severe depressive symptoms, clinically known as alcohol-induced affective disorder. Herein, the biochemical mechanism is that ethanol metabolites interact with 5-hydroxytryptamine (5-HT) to produce 5-hydroxyindoleacetic acid, which releases a large amount of 5-HT and norepinephrine (NE) in the brain, resulting in the decrease or even depletion of 5-HT and NE in the limbic system of the brain and leading to depression[1]. Proper antidepressant use can not only improve mood but also reduce desire to drink alcohol.

Sertraline, a serotonin reuptake inhibitor, increases 5-HT levels in the synaptic clefts of the brain and improves depressive symptoms. Shugan Jieyu capsules (SJC), a standardized botanical formulation (Hypericum perforatumand, Acanthopanax senticosus), demonstrate multimodal antidepressant actions through: The reuptake inhibition of 5-HT, dopamine, NE, and other neurotransmitters in the central nervous system, increasing the concentration of monoamine transmitters in the synaptic space, and inhibiting monoamine oxidase, thereby producing antidepressant effects[2]. While selective serotonin reuptake inhibitors (SSRIs) such as sertraline remain first-line antidepressants by blocking 5-HT reuptake, approximately 30% of patients exhibit inadequate treatment response, highlighting a critical need for novel therapeutic strategies[2]. Despite traditional use of SJC for "liver-soothing" in alcohol-related disorders, no randomized trials have evaluated its synergy with SSRIs.

Traditional Chinese medicine has a good therapeutic effect in the treatment of alcohol dependence, with few side-effects[3]. However, research on its combination with Western medicine to improve patients’ depression is insufficient. Currently, patients with alcohol dependence and depression are treated with the above-mentioned SSRIs[4]. This study addresses a critical evidence gap by conducting one of the first randomized controlled trial (RCT) examining the efficacy and safety of SJC-sertraline coadministration in alcohol-dependent patients with comorbid depression. Our findings may inform integrative treatment strategies for this high-risk population.

MATERIALS AND METHODS

Ethics statement

This study was approved by the institutional review committee (i.e., the Ethics Committee) of the Lishui Second People’s Hospital (date: December 16, 2021; No: 20211216-03). The study was conducted in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Participants

This study included 110 alcohol-dependent patients with depressive symptoms who were hospitalized at Lishui Second People’s Hospital between July 2022 and July 2024, accounting for 17.5% of all alcohol-dependent patients in the hospital. Sixty patients were ultimately included in the study after meeting the following inclusion criteria, as assessed by board-certified psychiatrists: (1) Met the diagnostic criteria for alcohol dependence in the International Classification of Diseases 10^th Edition[5-8]; (2) Had a Hamilton Depression Rating Scale (HAMD) score ≥ 17[4]; (3) Were aged 18-65 years; (4) Had not taken any antidepressant medication; (5) Had no serious primary physical disease; and (6) Had provided informed consent (through the patient or their family).

Study design

Sixty patients diagnosed with alcohol dependence and depression were randomly divided into two groups, with the observation period spanning six weeks. The control group (n = 30) received only sertraline monotherapy. According to the drug instructions, the initial dose was 50 mg/day, which could be increased to 100-150 mg/day depending on disease progression and individual patient tolerance, with an average dose of 118.7 ± 23.5 mg/day during treatment. For the study group (n = 30), in addition to the basic treatment of sertraline, SJC (produced by Chengdu Kanghong Pharmaceutical Company, at a dose of 0.36 g per capsule) were administered as two capsules twice a day, in the morning and evening. The average dose of sertraline was 113.1 ± 30.8 mg/day. Benzodiazepines were used as an adjunct throughout the study if a patient developed severe insomnia. There were no statistically significant differences in the general characteristics between the two groups; therefore, they were comparable.

Outcome measures

Patients in both groups were treated for a complete six-week treatment cycle, and efficacy of the treatment was evaluated during this period. The HAMD was used before treatment and at weeks 2, 4, and 6 during the treatment. The reduction rate of the HAMD score was calculated as follows: (Pre-treatment total score-post-treatment total score)/pre-treatment total score. A reduction rate ≥ 75% was defined as recovery, that of 50%-75% was defined as significant improvement, that of 25%-50% was considered progress, and that of < 25% was deemed ineffective. The total efficacy rate was calculated by summing up the percentage of participants who had recovered, those who had significantly improved, and those who had improved. Adverse drug reactions were assessed using the Treatment Emergent Symptom Scale at weeks 2, 4, and 6 following treatment.

Statistical analysis

Epidata 3.0 was used to input the data, and all data were statistically analyzed using IBM SPSS Statistics 23.0. The type of RCT analysis carried out was intention-to-treat. For continuous variables, the data were expressed as means ± SD and compared using independent sample t-tests. For categorical variables, the data were analyzed using χ² tests. The statistical significance level was set at P < 0.05, indicating that the difference was statistically significant.

RESULTS

Comparison of depression scores between the two groups

The study showed that approximately 56% of alcohol-dependent patients had depressive symptoms[9], and approximately 10.58% met the diagnostic criteria for major depression[10]. Before treatment, there was no significant difference in the HAMD scores of the two groups (P > 0.05). At the end of week 2 of treatment, the HAMD scores of the study group were significantly lower than those of the control group (P < 0.05). Additionally, HAMD scores remained consistently lower in the study group compared to those in the control group at the end of weeks 4 and 6 of treatment (P < 0.05). Intra-group comparisons showed that, from week 2 of treatment, the HAMD scores of the study group were significantly lower than those before treatment (P < 0.05). Meanwhile, the HAMD scores of the control group were significantly lower than those before treatment in week 4 (P < 0.05; Table 1).

Table 1 Intra-group comparisons of pre- and post-treatment depression scores (mean ± SD).

Group	n	Before treatment	At week 2	At week 4	At week 6
Control group	30	25.55 ± 4.93	23.00 ± 3.97	18.15 ± 4.19a	15.25 ± 4.67a
Study group	30	25.95 ± 4.26	19.65 ± 4.28a,b	14.10 ± 4.89a,b	11.35 ± 4.33a,b

^aP < 0.05 vs the scores before treatment.

^bP < 0.05 vs the scores of the control group.

Comparison of efficacy rates between the two groups

After comparing the reduction rate of HAMD scores before and after treatment, the study found that 10 participants were cured clinically, seven improved significantly, five improved, and eight experienced ineffective treatment in the control group. The total efficacy rate was 73.3%, and the inefficacy rate was 26.7%. In the study group, 12 participants were cured clinically, nine improved significantly, six improved, and three did not improve. The total efficacy rate was 90%, and the inefficacy rate was 10%. The χ² test showed a significant difference in the efficacy rates between the two groups (χ² = 4.812, P = 0.028; Table 2).

Table 2 Comparison of efficacy rates of the two groups after treatment.

Group	Number of effective cases	Number of ineffective cases	Total	χ2	P value
Control group	20	10	30
Study group	27	3	30	4.812	0.028
Total	47	13	60

Comparison of side-effect scores between the two groups

The participants reported a few side-effects, including dry mouth, nausea, constipation, and sweating. The degree of side-effects was mild, and participants were able to continue adhering to the treatment. The Treatment Emergent Symptom Scale scores were measured at weeks 2, 4, and 6 of treatment, and univariate analysis of variance showed no statistically significant differences in the scores between the two groups (P > 0.05; Table 3).

Table 3 Comparison of Treatment Emergent Symptom Scale scores (mean ± SD) of the two groups.

Period	Control group (n = 30)	Study group (n = 30)	F	P value
Week 2	6.25 ± 1.25	6.45 ± 1.43	0.423	0.767
Week 4	6.30 ± 1.45	6.25 ± 1.48	0.271	0.763
Week 6	5.05 ± 1.27	4.95 ± 1.43	0.058	0.943

DISCUSSION

The study’s findings showed that the study group (sertraline combined with SJC) experienced a strong antidepressant effect in the early stage of treatment (week 2), and their HAMD score was statistically significantly lower than that of the control group (sertraline alone). As treatment progressed, the HAMD score of the study group continued to decline and was significantly lower than that of the control group. The side-effects scale showed that no serious side-effects occurred in either of the two groups, indicating high safety, and there was no statistically significant difference in the incidence of side-effects between the two groups.

Further analysis of the results illustrated that the combination of sertraline and SJC had multiple advantages in the treatment of depression associated with alcohol dependence. First, the combination showed that significant antidepressant effects appeared at an early stage and persisted throughout the course of treatment. This suggests that combination therapy has a clear advantage in terms of stable and lasting improvements in patients’ moods. Long-term stable mood improvement is essential for the recovery of alcohol-dependent patients, as mood swings often trigger drinking behavior, thus creating a vicious cycle. Second, the safety of the combination of the two drugs has been supported by clinical data. Although some side-effects are often associated with antidepressant treatment, there were no serious side-effects in this study, regardless of whether sertraline was used alone or in combination with SJC. This finding is extremely significant for the selection of clinical treatment plans; it indicates that a combination of drug use can improve treatment efficacy and patient compliance without significantly increasing the drug burden on patients.

Additionally, from the biochemical mechanisms perspective, sertraline can increase 5-HT concentration in the synaptic gap by inhibiting 5-HT reuptake, while SJC can increase the concentration of multiple neurotransmitters through a multi-pathway mechanism of action, including the inhibition of the reuptake of 5-HT, dopamine, and NE and the inhibition of monoamine oxidase. This multi-mechanism synergistic action can more effectively regulate the function of the central nervous system and comprehensively improve patients’ depressive symptoms.

Notably, SJC, as a proprietary Chinese medicine preparation, have effective ingredients, including Hypericum transfoliata and Acanthopanax. This not only supports the traditional efficacy of these herbs in soothing liver depression and calming the mind, but also shows a unique mechanism of action in combination with modern pharmacological treatments. Hypericum transfoliata in the SJC can bind to presynaptic membrane receptors, increase intracellular concentrations of calcium and sodium ions, promote the release of neurotransmitters such as 5-HT1A, and be used in the postsynaptic membrane to improve the activity of 5-HT1A receptors, thus fighting symptoms of depression, such as anxiety and depression. Meanwhile, Acanthopanax protects dopaminergic neurons and prevents the apoptosis of nerve cells[11,12].

This study has several noteworthy limitations. Firstly, the study's sample size of 60 participants (30 per group) falls below the recommended threshold of at least 100 per group for detecting small-to-moderate effect sizes with 80% statistical power. This increases the risk of type II errors (failure to identify true effects) and reduces precision, as evidenced by wider confidence intervals for HAMD score reductions. Secondly, conducting the trial solely at Lishui Second People’s Hospital introduces selection bias and limits generalizability. Institutional-specific practices (e.g., sertraline dosing protocols) and regional patient demographics (e.g., predominantly rural population) may skew outcomes, hindering extrapolation to urban or multiethnic cohorts. Thirdly, the 6-week follow-up is insufficient to assess long-term outcomes such as depression relapse rates or alcohol recidivism, which typically manifest beyond 12 weeks. Delayed adverse events (e.g., hepatotoxicity from herb-drug interactions) may also remain undetected. Additionally, reliance on clinical scales (HAMD-17) without mechanistic biomarkers (e.g., serum 5-HT/NE levels, inflammatory cytokines) precludes validation of purported pharmacological synergies between sertraline and Shugan Jieyu. This obscures the biological basis of traditional Chinese medicine concepts such as liver-spleen harmonization.

CONCLUSION

These findings demonstrate that adjunctive SJC accelerate antidepressant onset (significant HAMD reduction from week 2 vs week 4 with monotherapy) and enhance treatment response (90% vs 73.3% response rate; P = 0.028) in alcohol-dependent patients with depression, without increasing adverse events. To validate these clinically meaningful benefits, multicenter trials with larger cohorts (n ≥ 200) should assess long-term outcomes (e.g., 6-month relapse rates) and integrate mechanistic biomarkers (e.g., monoamine metabolites, inflammatory cytokines) to elucidate synergistic pathways.

ACKNOWLEDGEMENTS

We thank the participants and families who participated. Special thanks to Jun-Jie Wang, Kai-Jie Fang and Wen-Ye Wu for their help with the formatting.