Heart failure (HF) can occur due to various causes, resulting in abnormal cardiac systolic and/or diastolic function (1). It is characterized by cardiac circulatory disorders and is an advanced stage of cardiovascular disease requiring long-term management (2, 3). Chronic HF (CHF) is marked by persistent symptoms such as dyspnea, fatigue, and fluid retention (4). Western medicine has an effective drug system for CHF that offers significant short-term symptom relief and improves laboratory indicators (5, 6). However, challenges in long-term management contribute to high mortality rates (7). CHF poses serious health risks and often leads to a poor prognosis, causing mental and physical strain that can result in depression (8). Additionally, depression can accelerate CHF progression and negatively affect outcomes, with both conditions acting as risk factors for each other (9).

Although Western medicine has developed a comprehensive drug system to manage CHF, limitations in long-term treatment remain, particularly in addressing the psychological burden of depression (10–12). However, Traditional Chinese medicine (TCM) believes that CHF combined with depression can be attributed to the “heart water” and “depression syndrome,” primarily caused by long-term deficiency of heart and kidney Yang, stagnation of qi activity, and stagnation of liver qi (13). Zhigancao decoction has been used historically to treat cardiovascular diseases, especially arrhythmias, and recent studies have suggested its potential benefits in improving cardiac function and reducing depressive symptoms (14–16). However, there is a paucity of clinical evidence on its efficacy in treating CHF combined with depression, which presents a significant gap in the current literature.

Therefore, in this study, we aimed to investigate the effects of Zhigancao decoction in patients with CHF and depression, focusing on its impact on clinical outcomes, cardiac function, inflammatory markers, and depressive symptoms. Our primary objective was to assess improvements in clinical efficacy and cardiac function. The secondary objective was to evaluate changes in depressive symptoms, quality of life, and levels of inflammation, addressing the need for more comprehensive treatment strategies for this dual condition.

CHF is the final pathological process in many cardiovascular diseases (19). Because the patient is in a chronic disease state, the course of the disease is repeated, the quality of life is reduced, and the economic burden is substantial; furthermore, chronic conditions are often complicated by depression, and poor heart function of the patient is accompanied by a higher probability of depression (20). Due to poor compliance with treatment recommendations, poor cardiac autonomic nerve function, aggravated inflammatory processes, thrombosis, and endothelial dysfunction, depression further worsens cardiac function and increases mortality in patients with CHF (21).

Currently, therapies for CHF complicated by depression mainly include drug therapy, psychological intervention, social support therapy, and exercise therapy. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are commonly used antidepressants, although their effects are unclear (22). However, TCAs have adverse cardiovascular side effects, including increased heart rate, induction of orthostatic hypotension, and slow ventricular conduction (23). One of the pharmacological characteristics of TCAs is their similarity to class I antiarrhythmic effects, which can block the sodium and potassium channels of the myocardial cell membrane, thus affecting the process of cardiomyocyte depolarization and repolarization (24). Moreover, studies have confirmed that TCAs have the risk of prolonging the QT interval and stimulating torsades de pointes (25). It also increases the risk of sudden cardiac death. In addition, some antidepressants have a long course of treatment, slow onset, drug resistance, high prices, and many adverse reactions; therefore, their clinical application is limited (26).

TCM believes that CHF belongs to the terminal stage of various cardiovascular diseases (27). The initial pathological development is mostly due to weakness of the heart and qi, and lack of blood circulation, resulting in decreased blood flow and blood stasis (28). TCM believes that the heart is the main blood vessel and is associated with consciousness, while the liver stores blood and regulates emotions. CHF leads to emotional depression, liver qi stagnation with multiple consequences, and poor qi (29). Therefore, the clinical treatment of CHF combined with depression benefits qi, promotes blood circulation, and relieves liver depression.

In the Zhigancao decoction recipe, raw Rehmannia is the monarch drug that nourishes Yin and blood (30). Simultaneously, Radix glycyrrhizae preparata, ginseng, Colla corii asini, Radix ophiopogonis, hemp seed, and jujube are ministerial drugs. The combined use of Glycyrrhizae preparata, ginseng, and jujube can benefit the heart and qi, and invigorate the spleen (31–33). The combination of Colla corii asini, Radix ophiopogonis, and hemp seed can nourish the heart Yin, and the heart and blood (34–36). Cassia twigs and ginger as the adjuvant, have the effect of warm heart Yang and promote blood circulation (37, 38). The drugs used together can benefit qi and nourish yin, and improve qi and blood, which can improve the depressive symptoms of patients with CHF (39).

LVEF is commonly used in clinical evaluation of cardiac function; LVEF is often abnormally decreased in patients with refractory HF, affected by vasospasm, increased myocardial load, and other factors (40). NT-proBNP is a marker of HF, and when the ventricle is stretched, changes in its tension can increase the release of NT-proBNP (41). MMP-9 is widely present in the myocardial tissue, and left ventricular cardiomyocytes may be the main source of MMPs in myocardial tissue (42). The expression level of MMP-9 is significantly increased owing to structural and compositional changes in the left ventricle of patients with CHF (43). hs-CRP is a non-specific inflammatory protein commonly used in clinical practice, and its levels can reflect the instability of vascular endothelial function (44).

In this study, the outcomes demonstrated that after therapy, the total effective rate for patients in the OG was elevated relative to that for patients in the CG; TCM symptoms and signs scores in OG were lower relative to those in CG; NT-proBNP, hs-CRP, and MMP-9 levels in OG were reduced relative to CG; PHQ-9 and SDS scores declined in OG relative to CG, LVEF level was higher in OG compared to CG, and MLHF score was lower in OG relative to CG. These data suggest that Zhigancao decoction could improve the clinical efficacy of patients with CHF combined with depression, reduce TCM symptoms and signs, promote cardiac function, reduce inflammation, relieve depression, and improve the quality of life. Consistently, it has been reported that Zhigancao decoction plus conventional medicine demonstrate good efficacy and fewer adverse reactions than conventional medicine in the treatment of arrhythmia (45). Yang et al. discovered that the combination of Chinese herbal medicines and conventional medical treatment increased the effective rate of cardiac function, reduced depressive status, and promoted the quality of life in patients with CHF complicated by depression (46).

There still exist some limitations in our research design. The key issues included a small sample size (122 patients) and a short intervention period (2 months), which may limit generalizability and obscure long-term effects. Additionally, reliance on subjective scales (e.g., PHQ-9, SDS) for depression assessment introduced potential bias. The abstract/introduction section lacked clarity on study design (e.g., whether it was randomized or observational) and deeper context on the shortcomings of current Western therapies for CHF with depression. In the future, improvements can be made to address this problem, such as a deeper analysis on key roles of individual herbal components (e.g., glycnsisitin A, one of the bicyclic peptides, as bioactive molecule of Zhigancao decoction for the treatment of CHF with depression) and potential placebo effects, especially given subjective outcome measures, to further evaluate the clinical efficacy of Zhigancao decoction and explore its underlying therapeutic mechanism, which may provide a theoretical basis for the treatment of CHF complicated with depression using TCM.

Based on Western medicine treatment, Zhigancao decoction can relieve the clinical symptoms and observation indicators of patients with CHF complicated by depression, which is valuable for clinical use. Nevertheless, larger randomized trials, extended follow-ups, and mechanistic studies are still needed for validating and expanding on our findings.