When East meets West: Accelerated depression recovery with Shugan Jieyu plus sertraline in alcohol-dependent patients

Abstract

Alcohol dependence with comorbid depression is a challenging issue. It often comes with low treatment adherence, slow responses to antidepressants, and high relapse rates. Recently, there has been growing interest in combining different approaches. traditional Chinese medicine has shown promise as a support alongside standard medication. In a double-blind, randomized, placebo-controlled trial involving 60 alcohol-dependent patients with comorbid depression, adding Shugan Jieyu capsules to sertraline resulted in earlier and significantly better symptom improvement compared to sertraline alone. The differences became noticeable as early as week two. The overall success rate was 90% in the combination group, while it was 73.3% for sertraline used alone (χ² = 4.812, P = 0.028), with no increase in side effects. These findings illustrate a promising example of “East meets West” synergy in psychopharmacology, where multi-target herbal modulation may accelerate recovery and improve tolerability. While these results merit cautious optimism, larger-scale, methodologically robust trials are needed to validate efficacy, safety, and pharmacokinetic interactions before broader clinical adoption.

Key Words: Sertraline; Shugan Jieyu capsule; Hamilton depression rating scale; Depression; Selective serotonin reuptake inhibitors; Traditional Chinese medicine

Core Tip: Combining Shugan Jieyu, a traditional Chinese herbal capsule, with sertraline significantly sped up and improved depression recovery in alcohol-dependent patients, with no extra side effects. This manuscript highlights the therapeutic potential and important considerations of integrating Eastern and Western methods to improve outcomes in complex dual-diagnosis cases.

TO THE EDITOR

Firstly, I commend Zhang et al[1] for their innovative investigation into Shugan Jieyu capsule (SJC) combined with sertraline in patients with alcohol dependence and comorbid depression. By demonstrating a striking early remission signal, the authors challenge long-held assumptions about selective serotonin reuptake inhibitor (SSRI) response latency and invite the field to reconsider how East-West integrative pharmacotherapy might reshape dual-diagnosis treatment. In the light of this work, I wish to offer several critical reflections and propose directions that may strengthen the scientific and translational value of this promising line of research.

A SHIFT IN DUAL-DIAGNOSIS TREATMENT

Alcohol use disorder and depressive disorders are among the most common mental health conditions. They often occur together more frequently than expected by chance[2,3]. The United States Food and Drug Administration has approved three medications for treating alcohol use disorder: Acamprosate, disulfiram, and naltrexone[4]. Both acamprosate and naltrexone help reduce alcohol intake and improve rates of abstinence, although the effects are usually modest[4]. Disulfiram has been used for a long time, but its effectiveness can vary. Other medications might also help reduce heavy drinking[4]. The anticonvulsants topiramate and gabapentin may lower alcohol intake, but there is not enough long-term research on their effects. Antidepressants do not reduce alcohol use in people without mood disorders, but sertraline and fluoxetine may help depressed individuals cut back on drinking[4]. In a randomized study by Zhang et al[1], SJC plus sertraline led to much faster remission of depressive symptoms compared to sertraline alone. The group receiving the combined therapy had a 90% overall effectiveness rate, while the rate for sertraline alone was 73.3%. It was also noted that patients taking SJC with sertraline showed much faster and greater improvement in their depression scores by the week 2 compared to those on sertraline alone. This significant acceleration suggests true pharmacodynamic synergy between SJC and sertraline. If this finding is confirmed, it could signal a major shift in treating both depression and alcohol dependence. We can then argue that this East-West combination could illustrate a paradigm shift where the multi-target action of SJC could enhance standard antidepressant therapy. This would suggest an additive or synergistic mechanism that needs urgent investigation.

An important debate surrounds the issue: Is the rapid response due to true pharmacodynamic synergy or an unknown pharmacokinetic interaction? On one hand, SJC’s ingredients, especially Hypericum perforatum (St. John’s wort), are known to have serotonergic and neurotrophic effects that might complement sertraline’s action[5,6]. On the other hand, Hypericum can induce liver enzymes (cytochrome P-450 3A4, etc.) and may alter drug levels[7,8]. If SJC were simply lowering sertraline concentration, we would not expect improved results. Thus, the clinical picture points to true multi-pathway synergy. Still, caution is needed: St John’s wort is known for its interactions and can increase the risk of serotonin syndrome when combined with SSRIs, affecting cytochrome P-450 metabolism[8]. Therefore, readers should maintain “cautious optimism”. The results are promising, but understanding the underlying mechanism (pharmacodynamics vs pharmacokinetics) is crucial for safety and broader application.

MECHANISMS AND UNRESOLVED QUESTIONS: PHARMACODYNAMICS VS PHARMACOKINETICS

Traditional Chinese medicine (TCM) formulations often target multiple pathways at once. SJC’s main ingredients are Hypericum perforatum and Acanthopanax senticosus. Recent studies indicate that SJC boosts central monoamines and it raises serotonin and dopamine while reducing hypothalamic-pituitary-adrenal axis hyperactivity[5,9]. Study by Fan et al[5] highlighted that hypericin (from Hypericum) has a clear antidepressant effect and have also noted that SJC “increases the secretion of dopamine and 5-HT”, which improves neural excitability. This matches the primary action of SSRIs, hinting at pharmacodynamic augmentation where two agents raise serotonin/dopamine via different routes which would yield an additive effect. However, a pharmacokinetic explanation could also be valid. Hypericum strongly activates cytochrome P-450 enzymes, and case reports caution that using it alongside SSRIs can lead to dangerously high serotonin levels[7]. Interestingly, the Zhang et al[1] trial found no increase in adverse events, indicating that SJC’s effect wasn’t just from hindering sertraline clearance. Without pharmacokinetic studies, it remains unclear whether SJC metabolites influence sertraline distribution or how they pass through the blood-brain barrier. Therefore, future research should explore this issue; for example, by measuring plasma sertraline levels in patients treated with SJC. Only by resolving this question can clinicians be sure that the observed quick antidepressant effect is a real therapeutic synergy and not a consequence of altered pharmacokinetics or serotonin syndrome.

CLINICAL EVIDENCE-MONOTHERAPY AND COMBINATION THERAPY

Clinical trials of SJC, whether used alone or with antidepressants, show promising but mixed results. In patients with depression and acute myocardial infarction, SJC alone performed similarly to sertraline; both groups had comparable remission rates, but SJC caused significantly fewer side effects[10]. Similarly, in cases of postpartum depression, one study reported single SJC had similar efficacy and better safety profile in comparison to regular antidepressants and when combined with regular antidepressants displayed even better efficacy rates without increasing adverse events[11]. Meta-analyses involving elderly or neurologically ill patients also support the use of SJC: For instance, a 2025 meta-analysis focused on late-life depression found that combining SJC with escitalopram greatly increased response rates [odds ratio (OR) approximately 4.25 vs SSRI alone; P < 0.00001] and led to larger reductions in Hamilton Depression Scale scores[6]. These findings suggest that SJC can improve standard SSRI therapy. On the other hand, some analyses urge caution. A 2023 meta-review involving patients with coronary heart disease reported that SJC alone was less effective than traditional antidepressants, including sertraline. This study noted poorer depression outcomes and an increased cardiac risk associated with SJC treatment[12]. In other words, SJC alone may not be as effective or safe as SSRIs. Thus, current evidence mainly supports SJC as an addition to treatment, rather than a replacement.

TCM FRAMEWORKS: BEYOND BIOCHEMISTRY

While Western pharmacology looks for specific molecular targets, TCM takes a broader, more holistic view. In TCM theory, depression especially when combined with alcoholism, is not just a simple “chemical imbalance” instead is a sign of disharmony among organs. The most common pattern is “liver qi stagnation with spleen deficiency”[13]. Alcohol abuse often puts more stress on the liver and spleen. Chronic drinking tends to stagnate the liver (leading to irritability and mood swings) and damages the spleen (impairing digestion and qi production)[5]. Therefore, a multi-target formula like SJC aims to soothe the liver and relieve depression, calm the mind, replenish qi, and invigorate the spleen[5]. This means that SJC is designed to “clear the heart spirit” while also harmonizing digestion and blood flow. This philosophy echoes in classical formulas: For example, Chaihu Shugan San (“bupleurum powder to soothe the liver”) contains ingredients that soothe the liver and invigorate blood while also strengthening the spleen and regulating qi[13]. These actions help relieve mood and physical symptoms. Similarly, Xiaoyao San (“free and easy wanderer”) was created to handle liver depression and spleen deficiency, reflecting the TCM belief that depression often shows a yin-yang imbalance in these organs[13]. Even formulas aimed at sadness and insomnia, like Kaixin San, focus on nourishing the heart (the center of the mind) and balancing qi[13]. When dealing with alcohol dependence, soothing the liver also metaphorically addresses the excess heat and stagnation caused by ethanol. Nourishing the spleen/stomach helps restore digestion and metabolic function after long-term use[13]. Although SJC is a modern proprietary mix, it is based on these concepts. Its Hypericum component clears “heat and fire toxin” from the liver-mind connection, while Acanthopanax strengthens qi and calms the spirit. By integrating these syndrome-differentiation principles, SJC showcases TCM’s interconnected approach, addressing multiple organ systems to improve both mood and physical symptoms.

CRITICAL PERSPECTIVES ON THE EVIDENCE

Despite these promising frameworks, the current evidence base is limited and methodologically weak. An editorial stance must be strict. First, the design of trials in most Chinese herbal medicine (CHM) research is inconsistent. In the SJC trial, the methodology was solid, but historically, many TCM randomized clinical trials lack proper standardization. For instance, one analysis of CHM trials found that important design elements, such as randomization method, allocation concealment, and blinding, were reported in fewer than 5% of studies[14]. Another review noted that less than 10% of herbal medicine trials used an appropriate randomization protocol[15]. These gaps raise concerns about bias; dropout rates, patient selection, and outcome assessment may be skewed or underreported. It is therefore recommended that the interpretation of SJC + sertraline results should include full transparency on these issues, ideally following consolidated standards of reporting trials CHM (CONSORT-CHM) guidelines.

Second, sample size and duration are problematic. The positive SJC study involved a small group, roughly 50 participants per arm, over several weeks. Compared to large multi-site SSRI trials, CHM trials typically have smaller participant numbers. A recent meta-analysis of CHMs for depression pointed out that many included trials were underpowered, with numerous studies having small sample sizes that limited the certainty of the current evidence[16,17]. Short durations, often ranging from 4 weeks to 8 weeks, are another limitation; alcohol dependence is chronic, and it is unclear whether the initial gains will last long-term. Any claim of accelerated recovery must be tempered by the question: Do these improvements last, or do symptoms return once TCM is stopped?

Third, publication and generalizability biases are significant. Almost all SJC data come from Chinese journals or investigators, which raises the likelihood of positive-reporting bias. It is well-known that favourable TCM results are much more likely to be published than negative findings. Additionally, patient populations in China, including their genetics, drinking habits, and concurrent TCM use, may differ from those in Europe or North America. We cannot assume that SJC’s effects will be the same across different ethnicities or healthcare systems. Finally, the quality of herbs varies. The bioactive content of any SJC capsule can depend on the plant source, harvest time, and manufacturing controls. Without strict standardization, such as assessing hypericin or other markers, reproducibility is not guaranteed. In short, it is encouraged that readers view the SJC + sertraline data to be promising but preliminary. Existing studies suffer from small sample sizes, potential bias, and short follow-ups[14,16,17].

ETHICAL AND REGULATORY CONSIDERATIONS

Clinicians and researchers should also pay attention to the regulatory status of SJC. Shugan Jieyu is approved in China but not in other countries. In China, it is licensed for treating mild to moderate depression[18]. However, it is not Food and Drug Administration or European Medicines Agency approved in Western practice. In many places, products based on Hypericum are sold as unregulated dietary supplements, which means their dose and purity can differ a lot. This creates safety concerns. A batch of SJC licensed in China has particular dosing and quality checks, while an imported version might not. Additionally, patients and regulators outside China may not be familiar with the ingredients and side effects of SJC. Therefore, it is recommended that any off-label use or trial of SJC in non-Chinese settings should be approached with caution. This should include strict ethics approval and monitoring of side effects. Maintaining a cautious optimism is essential. Although SJC combined with sertraline seems safe in published trials, we cannot assume the same level of safety in all situations.

TOWARD RIGOROUS, INTERNATIONAL TRIALS

In summary, the combination of Shugan Jieyu and sertraline provides a promising new approach for treating depression in alcohol-dependent patients. Its multi-target, East and West synergy might represent a significant change in strategy. However, promising evidence does not equate to proof. I conclude by urging action: We need to build on these findings with rigorous, international trials that follow CONSORT-CHM standards. Future studies should be well-powered, randomized, and double-blind, and clearly report all design elements. Importantly, they must include addiction-related outcomes; in addition to depression scores, trials should assess alcohol craving, consumption, abstinence rates, and relapse prevention. For instance, modern TCM trials on alcohol dependence focus on daily drinking and craving scales as primary endpoints[19]. These endpoints are vital for evaluating the effectiveness of dual-diagnosis treatment. Finally, funding and collaboration across regions will be essential. Multi-ethnic, multi-center trials, perhaps involving partnerships between Europe and China, would help address issues of generalizability and bias.

In supporting this agenda, I express a confident sense of urgency. The initial data suggest that SJC and sertraline may speed up recovery in a particularly challenging group. If confirmed, this would represent a promising union of ancient TCM knowledge and modern medication. Until then, we must maintain our commitment to scientific rigor; only through methodologically sound trials that comply with CONSORT-CHM and by including both psychiatric and addiction outcomes can we fully understand or challenge the potential of this east and west partnership.