Guanxinning for antipsychotic-induced cardiotoxicity: A critical appraisal of emerging evidence

Abstract

Antipsychotic drug induced cardiotoxicity is an important and unresolved clinical complication, with few preventive strategies beyond routine monitoring. A recent randomized, double-blind, placebo-controlled trial conducted by Luo et al. claimed that the traditional Chinese medicine Guanxinning might improve cardiac electrical parameters, function, and circulating biomarkers in schizophrenia patients with long-term use of antipsychotic drugs. However, the findings of their research based on surrogate endpoints in schizophrenia patients without cardiovascular disease limit their generalizability and clinical significance. The cardioprotective mechanisms, such as anti-inflammatory and antioxidant effects, are mostly inferential without direct molecular validation. This review focuses on the evidence that Guanxinning may be used as an adjunct to alleviate cardiac injury caused by antipsychotic drugs. For high-risk populations, larger-scale multicenter studies are needed to observe meaningful cardiovascular disease outcomes and confirm the therapeutic value of Guanxinning.

Key Words: Guanxinning; Antipsychotic drugs; Cardiac function; Protective role; Clinical implications

Core Tip: Guanxinning may have a certain effect on improving cardiotoxicity caused by antipsychotics. Some trials have found that long-term use of antipsychotics can affect cardiac electrophysiology, myocardial function and biomarkers. However, these findings are based on surrogate indicators and the study subjects have no prior cardiovascular disease, so their limitations are relatively large. Current evidence is not sufficient to support routine use, and its benefits are still in the preliminary stage. Larger-scale studies targeting high-risk populations and observing cardiovascular disease outcomes are needed to clarify the effect.

INTRODUCTION

Mental illnesses are chronic conditions associated with severe functional impairment and reduced quality of life. These disorders have a prolonged course and high recurrence rate, adding a burden to patients’ families and society[1]. In the long-term management of mental disorders, antipsychotic drugs are the basic therapy for controlling psychotic symptoms[2,3]. Although long-term use of antipsychotic drugs can control symptoms to keep schizophrenia patients stable[4], increasing evidence shows that these factors are related to various adverse cardiovascular events, which are the main cause of excess mortality in this population[5].

Antipsychotic drug cardiotoxicity involves three related areas, including electrophysiological aspects, clinical aspects, and pathophysiological changes[6,7]. From the electrophysiological aspect, the main pathology of arrhythmia is that the drug-induced rapid delayed rectifier potassium current is blocked, which prolongs the corrected QT interval. This change increases the risk of ventricular tachycardia such as torsades de pointes, and also worsens the instability of myocardial repolarization. The detectable electrocardiographic abnormalities in the clinic are only preliminary signs of sudden cardiac death[8]. Antipsychotic drugs directly damage cardiac cells, induce oxidative stress, and maintain an inflammatory state at the structural/functional level, and they may also promote the development of cardiomyopathy[9]. High levels of cardiac troponin I and B-type natriuretic peptide in the blood indicate that the heart is working harder and there is microscopic myocardial damage[10]. People who take psychiatric drugs for a long time, due to the accumulation of pathophysiological changes, have a higher incidence and mortality rate of prior cardiovascular disease, which is the main reason for their shorter lifespan[11-13]. Although risk awareness is gradually increasing, most current management strategies focus on monitoring without prevention, and there are no effective cardioprotective measures for people at high risk of cardiovascular disease.

There has been increased interest in the cardiac injury caused by adjuvant antipsychotic drugs. Guanxinning is a traditional Chinese medicine (TCM) containing some potential cardioprotective agent, such as tanshinone and tetramethylpyrazine. Preclinical evidence and limited clinical data also show that these compounds may have multi-target effects (such as regulating oxidative stress, inflammatory pathways, vascular function)[14,15]. However, most of the understanding of these mechanisms comes from experimental models or individual clinical observations, and their association with the cardiotoxicity of antipsychotic drugs in humans has not been fully clarified.

Luo et al[16] recently conducted a randomized, double-blind, placebo-controlled trial that explored the potential role of Guanxinning in patients with schizophrenia taking long-term antipsychotic medications. The study reported that cardiac physiological parameters, functions and biomarkers improved to a certain extent. However, most findings are based on surrogate endpoints in a population without cardiovascular disease, which limits its application in high-risk clinical scenarios.

This review aims to investigate the role of Guanxinning in preventing and treating antipsychotic-induced cardiac injury, focusing on its benefits, mechanisms, and limitations, placing the research findings in the context of cardiotoxicity management, to understand whether Guanxinning is a feasible adjunctive therapy or requires more investigation.

DEVELOPMENTS AND CONTROVERSIES IN THIS FIELD

In recent years, the academic understanding of the cardiotoxicity mechanism of antipsychotic drugs has shifted from a single channel to a multitarget network[17,18]. Accumulating evidence shows that second-generation antipsychotics have improved in vitro side effects compared to first-generation antipsychotics, but there is still a clinically significant risk of cardiotoxicity[19,20]. However, new advances in mechanistic studies show that different drugs have different inhibitory potentials on human ether-a-go-go related gene (hERG) channels (measured by the half maximal inhibitory concentration/maximum plasma concentration, free ratio)[21]. Drug-induced modulation of other ionic currents, such as sodium and calcium, enhances or counteracts the inhibition of hERG, thus explaining the differences in arrhythmia risk between drugs[22,23]. To be used for interpreting mechanistic differences, the cardiac toxicity of common antipsychotic drugs, including hERG inhibitory potential, QTc prolongation risk, other ion channel effects, and clinical considerations, are summarizes in Table 1.

Table 1 Comparative cardiotoxicity of commonly used antipsychotic drugs.

Drug class	Drug name	hERG inhibition (IC50/Cmax, free)	QTc prolongation risk	Other ion channel effects	Clinical considerations	Ref.
First generation	Haloperidol	High (< 5)	High	Na+ blockade (mild)	High-risk patients require ECG monitoring	[57]
Second generation	Risperidone	Moderate (approximately 10)	Moderate	K+ blockade	Dose adjustment in renal impairment	[58]
Second generation	Olanzapine	Low (> 20)	Low	Ca2+ blockade (mild)	Monitor metabolic parameters	[59]
Second generation	Quetiapine	Moderate (approximately 12)	Moderate	Na+/Ca2+ blockade	High-dose usage may prolong QTc	[60]

hERG: Human ether-a-go-go related gene; IC₅₀: Half maximal inhibitory concentration; Cmax: Maximum plasma concentration; QTc: Corrected QT; ECG: Electrocardiogram.

Cardiotoxicity changes from electrophysiological abnormalities to structural damage[24]. Research indicates that antipsychotics can induce oxidative stress and inflammatory responses, leading to myocardial cell damage, left ventricular dysfunction and even cardiomyopathy[25,26]. Recent studies summarized the cardiovascular side effects of psychotropic drugs[27,28], showing conditions ranging from autonomic nervous system dysfunction and malignant ventricular arrhythmias to cardiomyopathy and thromboembolic events[29]. Cross-sectional study shows that many patients with mental disorders taking antipsychotics have abnormal electrocardiograms; among them, QTc interval prolongation is a relatively obvious phenomenon[30]. Cardiovascular disease is one of the main causes of death in patients with severe mental illness[31-33], which is caused by a complex mixture of biological, patient-specific and healthcare system factors[34].

Regular electrocardiographic monitoring is recommended, but actual compliance is not high, and the significance and management of mild QTc prolongation are still under debate[35]. Adjustment of the treatment plan is difficult. For patients with cardiac injury, clinical decisions need to make a difficult trade-off between changing and adding drugs. Switching to drugs with lower cardiovascular risk may reduce cardiovascular risk but also cause fluctuations in psychiatric symptoms[36]. Adding cardiovascular protectants to the treatment regimen can trigger drug interactions and concerns about adherence. This therapeutic dilemma indicates that clinicians have not properly balanced psychological stability and cardiac safety, these limitations need to be addressed. Some researchers pointed out that the abuse of antipsychotics (such as off-label use) will worsen public health, but there is a lack of effective strategies to reduce cardiometabolic side effects[37-40]. Although Luo et al[16] have new views on mental illnesses, core controversies have also emerged. They excluded all patients with baseline cardiac dysfunction, so the conclusions drawn cannot be directly used to guide clinical practice for high-risk groups who most need intervention. The efficacy and safety of Guanxinning in patients with QTc prolongation or heart failure are not yet clear. Many of its components make the mechanism of action relatively complex. Whether cardio protection is a single pathway or multi-target, and the interaction between active ingredients (tanshinone and tetramethylpyrazine) and the toxic mechanism of antispermatogenic drugs remain unclear. The anti-atherosclerosis test of Guanxinning confirms that it is beneficial to the cardiovascular system[16]. However, research into its mechanism of action (antithrombotic, anti-inflammatory, and endothelial protection) is still at the initial stage and has not yet reached the molecular level.

CRITICAL APPRAISAL OF THE STUDY

Luo et al[16] adopted a randomized, double-blind, placebo-controlled design, which is a methodological advantage and lays a foundation for preliminary assessment. Guanxinning combination therapy is associated with improvements in cardiac parameters, such as QT interval, left ventricular ejection fraction, and biomarkers of myocardial injury or inflammation[16]. The study showed that long-term use of antipsychotics may have potential cardioprotective effects[16]. However, some important limitations limit the interpretation of the results and their clinical application. First, the baseline cardiac function of the study population was normal, and those with previous cardiovascular disease or significantly prolonged QTc were excluded. Therefore, the results may not apply to high-risk populations, who could have benefited from cardioprotective measures. Second, the study relied on surrogate endpoints such as electrophysiological parameters, such as electrophysiological parameters and biomarkers, rather than clinically meaningful outcomes such as arrhythmia incidence, heart failure events, and cardiovascular disease mortality. These surrogate markers may reflect early cardiac changes, but direct translation into improved long-term clinical outcomes is uncertain. This limitation is related to cardiotoxicity induced by antipsychotic drugs, because the relationship between QTc prolongation and adverse clinical events is complex and not fully determined. The cardioprotective mechanisms of Guanxinning are not certain. Oxidative stress, inflammatory markers, and myocardial injury biomarkers are reduced, but molecular pathways, target binding, or pharmacokinetic-pharmacodynamic aspects have not been directly explored. The multicomponent nature and unclear mechanism of Guanxinning limit the establishment of a causal link between biologically active ingredients and clinical effects. The study did not elaborate on the type/dose stratification of antipsychotic drugs, and antipsychotic drugs differ in cardiotoxicity. The drug interaction between Guanxinning and antipsychotic drugs has not been systematically evaluated. A single-center design and small sample size may cause bias and limit external validity.

Although Guanxinning may improve alternative cardiac markers[41,42], it is not enough to support the routine use of Guanxinning in preventing antipsychotic-induced cardiotoxicity. More multicenter trials are needed, including high-risk populations and clinically relevant cardiovascular endpoints, to determine its true therapeutic value.

CLINICAL IMPLICATIONS

Management of cardiotoxicity induced by antipsychotics remains a major clinical challenge, especially for patients who require long-term treatment. Current strategies mainly focus on risk assessment and routine monitoring, such as electrocardiographic monitoring, rather than actively taking cardioprotective measures[43,44]. The potential role of adjuvant therapy in this regard has received increasing attention.

Luo et al[16] showed that among patients receiving antipsychotic treatment, Guanxinning may be associated with improvements in cardiac electrophysiological parameters, myocardial function, and circulating biomarkers. These observations suggest that Guanxinning may be an adjuvant strategy to alleviate early or subclinical cardiac changes. However, it should be noted that most evidence only involves surrogate endpoints and comes from populations without baseline cardiovascular disease. Whether these improvements can reduce the risk of clinically significant outcomes such as arrhythmia, heart failure, or cardiovascular disease mortality remains unclear. Guanxinning is an investigational adjunctive therapy in clinical practice and not a standard treatment. It should not replace existing risk management measures, such as using antipsychotics cautiously, optimizing doses, and regularly monitoring cardiovascular disease. Due to the lack of robust data on drug interactions and long-term safety, clinicians need to be cautious when using Guanxinning in patients with heart disease or those taking multiple medications. However, the potential multitarget properties of Guanxinning may have conceptual advantages in addressing complex, multifactorial antipsychotic-induced cardiotoxicity[14,45-47]. This means that well-designed clinical trials are needed to clarify its effects, especially in high-risk populations and compared with existing cardioprotective strategies[43,48].

COMBINING EASTERN AND WESTERN MEDICAL APPROACHES TO MANAGE COMPLEX ILLNESSES

In modern medical practice, complex conditions such as psychiatric disorders often necessitate multidimensional, multitargeted intervention strategies to manage associated cardiovascular complications. While antipsychotic medications effectively control psychotic symptoms, their side effects have become a significant concern in clinical treatment[37]. Luo et al[16] demonstrated that combining the TCM Guanxinning with chlorpromazine significantly improved cardiac electrophysiological parameters, enhanced left ventricular ejection fraction, reduced myocardial injury markers, and suppressed oxidative stress and inflammatory responses. This advantage is by no means an isolated case. In cardiovascular disease, there is evidence that integrated treatment of atherosclerotic lower limb arterial occlusive disease using TCM, including herbal medicine, acupuncture, and dietary therapy, and drugs such as paclitaxel or rapamycin, is more effective than Western medicine alone[49]. This integrated approach produces synergistic effects in improving microcirculation and regulating blood lipids, resulting in fewer adverse reactions The network meta-analysis indicates that TCM combined with conventional Western medicine is more efficacious in treating type 2 diabetes than Western medicine alone, providing evidence for optimizing clinical treatment strategies[50]. The integration of TCM and Western medicine has demonstrated potential in cardiovascular medicine and in the management of cardiovascular risks associated with metabolic disorders[50]. For example, a systematic review incorporating multiple randomized controlled trials indicates that, in patients with diabetes and coronary heart disease, TCM compound Yiqi Yangyin Huoxue decoction in conjunction with conventional metformin treatment can significantly improve blood glucose, blood lipids, and electrocardiogram parameters, while enhancing overall therapeutic efficacy[51]. In the comprehensive management of diabetes, combined TCM and Western medicine can more effectively reduce fasting blood glucose and glycated hemoglobin levels, while simultaneously improving quality of life[52,53].

These findings demonstrate the modern pharmacological value of TCM under its traditional theory of “promoting blood circulation, removing blood stasis, unblocking vessels, and relieving pain”[54], and highlight the unique advantages of integrated TCM and Western medicine in managing complex diseases. Western medicine excels in precise diagnosis and targeted intervention, while TCM is good at holistic conditioning and multitarget protection. The organic integration of the two improves the curative effect and achieves the effect of addressing both the symptoms and root causes in terms of pathological mechanisms[55]. This method stabilizes mental symptoms, reduces drug side effects, and improves patients’ quality of life and long-term prognosis[56]. Therefore, promoting integrated TCM and Western medicine treatment regimens is a major trend in current clinical practice.

FUTURE DIRECTIONS

To evaluate the safety and effectiveness of Guanxinning, trials need to target high-risk cardiovascular populations, such as those with mild heart failure, multiple cardiovascular risks, or prolonged QTc. Phase 2 trials will focus on expanding to patients with mental illnesses requiring long-term antipsychotic treatment, such as patients with bipolar disorder and depression. This will enable the treatment to address more than one mental illness. Mechanistic studies should use cohorts such as patients with major depressive disorder or bipolar disorder who require long-term antipsychotic treatment. By moving from phenotypic association to causality, researchers can use molecular biology and omics technologies to study the regulation of specific signaling pathways by active compounds such as tanshinone and tetramethylpyrazine. This could deepen our understanding of the relationship between the cardioprotective mechanism of Guanxinning and the cardiac injury caused by antipsychotics.

CONCLUSION

Antipsychotic-induced cardiotoxicity is a clinical phenomenon, with relatively few preventive measures. New evidence suggests that during long-term use of antipsychotics, Guanxinning may alter cardiac parameters, myocardial function, and biomarkers. However, these findings are based on studies of surrogate endpoints and low-risk populations, limiting their clinical application. Current available evidence does not support the routine use of Guanxinning to prevent antipsychotic-related cardiac injury. The reported benefits are currently unclear. Its impact on clinically relevant cardiovascular outcomes remains unclear. In high-risk populations, the efficacy and potential mechanism of action are also unclear. Overall, Guanxinning may serve as an adjuvant drug, but its clinical effects need to be confirmed, so interpretation should be cautious.