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Introduction

Antipsychotics are the most commonly prescribed psychotropic medications in the treatment of mental disorders, especially schizophrenia. In addition to their therapeutic effects, antipsychotics also have side effects. Overweight and obesity are among these side effects, especially with atypical antipsychotics.¹ Hakami et al studied 395 patients divided into 2 groups, group 1 used antipsychotics without metformin, group 2 included 86 patients using antipsychotics with metformin, the authors found that in group 1, the rate of weight gain was 64.4% and in group 2 was 38.37%.² Torres et al studied 244 patients with a first psychotic episode treated with antipsychotics. They found that after 3 years of follow-up, the rate of metabolic syndrome in the patient group increased from 6.6% at baseline to 18.3%, while the rate in the control group was 5.4% and 8.1%, respectively.³ The rate of metabolic syndrome in Corell’s study was 37.3% among 367 patients treated with second-generation antipsychotics.⁴ Overweight and obesity in patients elevate the risk of cardiovascular diseases, metabolic syndrome, type 2 diabetes, dementia, and other chronic diseases, as well as increase mortality, reduce the quality of life in patients. In women, the risk of overweight and obesity could be heightened due to physiological and endocrine factors, including hormonal changes during the menstrual cycle, pregnancy, and menopause. In addition, women tend to accumulate more central fat than men, increasing the risk of abdominal obesity. In addition to weight gain and obesity, menstrual disorders, including amenorrhea due to antipsychotics, were also common among women. Savarimuthu et al confirmed the role of antipsychotics in causing amenorrhea in female psychotic patients, and the authors identified factors associated with amenorrhea as antipsychotic use for more than 2 years and treatment by risperidone.⁵ Literature and many studies have shown that antipsychotics that antagonize dopamine receptors in the tuberoinfundibular and limbic systems increase blood prolactin levels, which is the main mechanism for causing menstrual disorders in female patients.^6,7 The combination of antipsychotic use and these gender factors poses a major challenge in the management of mental health and overweight in female patients.

The relationship between schizophrenia and metabolic disorders is complex, as psychiatric symptoms may exacerbate these side effects. Negative symptoms, such as reduced motivation and social withdrawal, and cognitive impairments common in schizophrenia can lead to sedentary lifestyles, poor dietary habits, and irregular daily routines, all of which contribute to weight gain and metabolic syndrome. Conversely, metabolic abnormalities such as weight gain, dyslipidemia and diabetes mellitus, may influence cognitive and social functioning, potentially exacerbating psychiatric symptoms. For instance, Sayed et al (2023) found that total cholesterol and triglyceride levels were negatively correlated with social cognition in psychotic patients, suggesting that metabolic changes may be influenced by the severity of psychiatric symptoms.⁸ These factors, combined with the pharmacological effects of antipsychotics, may amplify the risk of obesity and related complications, necessitating a comprehensive approach to patient care that addresses both mental and physical health.

In Vietnam, data on overweight, obesity, and menstrual disorders among female patients using antipsychotics are limited. Currently, in the databases available on the internet, we have not found any studies reporting the effects of antipsychotic medications on patients’ weight, BMI, or menstrual cycles. Assessment of the impact of antipsychotics on the change of weight, obesity, and amenorrhea in these participants plays an important role in developing timely prevention and intervention strategies. Based on the above situation, this study was conducted to evaluate the change of weight, BMI, and amenorrhea as well as several laboratory tests among female inpatients using antipsychotics, thereby proposing effective management and health care measures for this group of participants.

Subjects and Methods

Subjects

The study population consisted of female schizophrenic inpatients over 18 years old at Tien Giang Psychiatric Hospital, Vietnam, from May 2023 to May 2024 who had been prescribed antipsychotics for at least three months before admission. To provide further detail on pretrial antipsychotic use, medical records were reviewed to confirm the types and duration of antipsychotics used prior to enrolment; however, specific details such as exact dosages were not uniformly available due to variability in pretrial records. These patients or guardians agreed to participate in the study after being fully explained about the research procedure and signing a consent form. Participants were selected using a non-probability, consecutive, convenience sampling approach. Exclusion criteria encompassed pregnant or lactating individuals, primary amenorhea, those with severe liver or kidney dysfunction, patients with cancer or significant cognitive impairment precluding interview participation, and those concurrently using other psychotropic medications, such as mood stabilizers or antidepressants, during the treatment period. Based on these criteria, a total of 60 inpatients were enrolled during the study period.

Methods

This was a 12-week longitudinal prospective study. We assessed the weight, BMI, and amenorhea of the patients at two time points: at baseline (T0) and 12 weeks later during follow-up (T1). To classify overweight and obesity, we use the IDI and WPRO standards based on BMI for Asians as follows: underweight BMI <18.5 kg/m², normal: BMI = 18.5 −22.9 kg/m², overweight: BMI = 23–24.9 kg/m² and obese: BMI from 25 kg/m² or higher. Amenorrhea is defined as the absence of menstruation for at least 90 days. In addition, some biochemical tests and clinical indicators were also measured, such as blood pressure, waist circumference, fasting blood glucose (FBG), triglycerides, and HDL-C at baseline and after 12 weeks of follow-up. The results of biochemical tests were statistically analyzed in two ways: method 1 compared the results of biochemical tests according to the classification of the components of metabolic syndrome, and method 2 compared the mean of test results at 2 time points: baseline and 12 weeks of follow-up. We used patients’ medical records and a structured questionnaire to survey patient demographic characteristics and previous medical history. Patients with abnormalities in blood pressure, diabetes, and obesity at the baseline would be consulted with internal medicine doctors and treated with medications, exercise, and nutrition regimens as prescribed by these doctors.

Statistical Analysis

All statistical analyses were performed using SPSS version 20.0. For descriptive data, frequencies and percentages were used. In statistical analysis, we used the McNemar test and the paired t-test to compare the proportions and mean values of variables at baseline and after 12 weeks of follow-up, respectively. A p-value <0.05 was considered statistically significant.

Results

Participant Characteristics at the Baseline

The mean age of the participants was 36.83 (min 17, max 53), the mean BMI at the baseline was 22.50 ± 2.29, of the 60 patients, 7 patients (11.7%) were classified as obese, 24 patients (40.0%) were overweight, and 1 patient (1.7%) had amenorhea at baseline. Some clinical characteristics and biochemical test indices at baseline in the study subjects were as follows: waist circumference ≥ 80 cm (81.7%), blood pressure ≥ 130/85 mmHg (38.3%), triglyceride ≥ 150 mg/dL (45%), HDL < 50 mg/dL (25%), fast blood glucose ≥ 100 mg/dL (6.7%) (Table 1).

63.3% of patients had used antipsychotics for more than 24 months, 25% of patients used 2 types of antipsychotics, and olanzapine and risperidone were the two most commonly used antipsychotics, with rates of 48.3% and 65%, respectively (Table 2).

Table 2 Characteristics of Using Antipsychotics Among Participants

Compared to the baseline, the weight, the mean BMI, rates of obesity, amenorhea, and waist circumference of 80 cm or more among study subjects all increased significantly, while the proportion of patients with HDL-C below 50 mg/dL decreased significantly after 12 weeks of follow-up. Other parameters, such as blood pressure, fasting blood sugar, and triglycerides, showed no significant change compared to the baseline (Table 3).

Table 3 Changes in Weight, BMI, Amenorhea, Some Clinical Characteristics, and Biochemical Tests (Being Classified According to the Components of Metabolic Syndrome) at 12-Week Follow-Up Compared with Baseline

The mean values of waist circumference, total cholesterol, HDL-C, LDL-C, and Triglyceride all increased significantly, while the mean values of diastolic blood pressure and systolic blood pressure all decreased significantly; only the average value of blood sugar did not change significantly at 12 weeks of follow-up compared to baseline (Table 4).

Table 4 Mean Changes in Waist Circumference, Biochemical Tests, and Blood Pressure at Baseline and After 12 Weeks of Follow-Up

To explore factors associated with metabolic syndrome components, we conducted a multivariate regression analysis examining age, duration of antipsychotic use, and number of antipsychotics used, but no statistically significant associations were found.

Discussion

The results in our Table 1 showed that at the baseline time, 49 patients (81.7%) had a waist circumference of 80 cm or more, 24 patients (40%) were overweight, and 7 patients (11.7%) were obese. In our selection criteria, patients had to have used antipsychotics 3 months before admission, so these effects could also be caused by previous use of antipsychotics. Furthermore, patients with schizophrenia may have negative symptoms, so a lack of exercise, an unbalanced diet, and irregularity can also lead to these manifestations. For these patients, right from the time of admission, we consulted with endocrinology, metabolism, and nutrition experts to advise on treatment drugs, exercise, and nutrition regimens for the patients.

The effects of antipsychotics, especially second–generation medications, on weight gain, obesity, and metabolic syndrome have been demonstrated by many researchers.^9–11 Ye et al in a systematic review found that antipsychotics cause overweight, metabolic syndrome, and obesity through various mechanisms such as genetics, effects on the central nervous system, neuroendocrine system, and even the gut microbiota.¹² Mortimer Katherine et al, in a mini-review article, reported a 3-fold increased risk of metabolic syndrome in people using antipsychotics.¹³ In a systematic review and meta analysis, Pillinger et al found that with weight change, including 83 studies with 18,750 patients, weight gain was demonstrated in patients using brexpiprazole, risperidone and paliperidone, quetiapine, iloperidone, sertindole, olanzapine, zotepine, and clozapine, of which clozapine caused the most weight gain. Also in this study, when comparing with placebo on BMI change, the authors found that drugs that significantly increased BMI compared with placebo included lurasidone, risperidone and paliperidone, quetiapine, sertindole, clozapine, and olanzapine. Of these, olanzapine was the drug that increased BMI the most.¹⁴ Our study results in Table 3 on weight change and BMI were also consistent with the study results of other authors. Prevalence of patients with BMI ≥25 kg/m² increased from 7 patients (11.7%) at baseline to 29 patients (48.3%) at 12 weeks of follow-up. In our study, 39 patients were treated with risperidone and 29 patients were treated with olanzapine (either monotherapy or in combination). The literature has shown that second-generation antipsychotics are associated with a risk of weight gain.¹⁵ However, in our study, only one patient used clozapine, limiting our ability to assess its specific impact on weight gain and metabolic changes. While we reported an increased prevalence of metabolic syndrome components as a risk factor for cardiovascular diseases, the short-term changes observed over 12 weeks may not directly lead to cardiovascular events but contribute to long-term cardiovascular risk.¹⁵ Furthermore, non-pharmacological factors, such as improvements in psychiatric symptoms and the structured environment of inpatient care (eg, regular meals and reduced agitation), may also contribute to metabolic changes, such as increased appetite or weight gain, independent of antipsychotic effects. Due to the absence of longitudinal data on psychiatric symptom severity in our study, we could not directly analyse the relationship between symptom improvement and metabolic outcomes. The side effect of weight gain of antipsychotic drugs occurs not only in adults but also in adolescents. Taylor et al studied 119 children aged 8–19 years with a diagnosis of schizophrenia and schizoaffective disorder treated with molindone, risperidone and olanzapine and found that after 8 weeks, the mean weight gain was 0.74 ± 3.51 kg, 4.13 ± 3.79 kg, 7.29 ± 3.44 kg compared to baseline for molindone, risperidone and olanzapine, respectively.¹⁶ In our study, all patients were taking second-generation antipsychotics, with 3 patients (5%) taking a second-generation antipsychotic in combination with a first-generation antipsychotic (levomepromazine combined with olanzapine) (Table 2). Kalebie et al analyzed 25 studies with 4064 patients treated with antipsychotics in Africa and found that the prevalence of metabolic syndrome was 22% and that risk factors were female sex, older age, and increased BMI.¹⁷ Other meta-analyses have confirmed these results. A multi-treatment meta-analysis by Leucht et al found that all antipsychotics except haloperidol, lurasidone, and ziprasidone were associated with weight gain.¹⁸ Olanzapine and zotepine were significantly more associated with weight gain than the other drugs¹⁸ In addition, changes in weight, BMI, and some components included in the diagnostic criteria for metabolic disorders, including a waist circumference of 80 cm or more and HDL-C <50 mg/dL, also changed significantly at 12 weeks of follow-up compared to baseline (Table 3). Similarly, Pillinger et al also found that antipsychotic drugs had significant effects on changes in the concentrations of total cholesterol, triglycerides, HDL-C, LDL-C and glucose concentration; olanzapine and clozapine were shown to be most commonly responsible for these effects.¹⁴ Our study results in Table 4 showed that the average of waist circumference, triglycerides, total cholesterol, LDL-C, and HDL-C all increased significantly at 12 weeks of follow-up compared to baseline. Meanwhile, the average values of systolic blood pressure and diastolic blood pressure decreased significantly, and fast blood glucose remained unchanged at 12 weeks compared to baseline. The reason for this result is that blood pressure is monitored daily, so when we detect any patient with signs of hypertension, we consult with an internal medicine doctor and use medication to treat hypertension for the patient. The medication used in these patients was calcium channel blockers such as amlodipine. The mechanism of weight gain, obesity, and changes in metabolic syndrome components has been established through many studies. Weight gain with antipsychotics is thought to be due to their effects on serotonin 5-HT2A and 5-HT2C, dopamine D2 and D3, histamine H1, and muscarinic M3 receptors. The degree of weight gain varies among antipsychotics depending on their affinity for these receptors. Antipsychotics also affect neuropeptides involved in appetite control and energy metabolism. Leptin and adiponectin, adipokines produced in white adipose tissue, have been linked to antipsychotic-induced weight gain. Increased leptin and decreased adiponectin have been found in patients treated with short-term and long-term olanzapine.⁹ As mentioned above, patients with obesity, hyperglycemia, and overweight were consulted with endocrinologists and nutritionists to receive appropriate medication and lifestyle, and diet treatment. However, the proportion of patients with a waist circumference of 80 cm or more continued to increase, and other bilanlipides indices also changed in a negative direction at the 12-week follow-up period (Table 4). This may be due to several reasons. First, reducing waist circumference requires regular and persistent exercise, which is difficult to do with schizophrenic patients in the acute phase, regardless of whether they have negative or positive symptoms. The second reason may be that the continued effects of antipsychotics cause weight and metabolic problems in patients who have not shown these signs at the beginning. These reasons are clearly demonstrated by the results of Table 3. Weight changes, obesity, and components of the metabolic syndrome during treatment with antipsychotic drugs increase the risk of cardiovascular and metabolic diseases in patients, increasing mortality. Cardiometabolic diseases are often associated with a high risk of cognitive and social function impairment in psychotic patients. Sayed S.E in a case-control study of 150 psychotic patients and 120 healthy controls found that total cholesterol and triglyceride levels were negatively correlated with the interpersonal domain of social cognition and total cholesterol levels were positively correlated with the total score of social function.⁸ In addition, for women, appearance is important, so being overweight or obese affects the self-esteem and confidence of schizophrenic patients who already have many complexes and stigmas due to the mental illness itself, which can lead to depression, reduced quality of life, non-compliance with treatment, and even suicide. Therefore, in clinical practice, psychiatrists also need to detect these problems early and work in a multidisciplinary team to support and resolve these problems for patients early, improving the above consequences.

In addition to changes in weight, BMI, and some components of metabolic syndrome, our study results in Table 3 also showed a statistically significant increase in amenorrhea in the study subjects at 12 weeks of follow-up compared to baseline, with rates of 25% and 1.7%, respectively. Many previous studies have also shown a relationship between menstrual disorders, including amenorrhea, and the use of antipsychotics. Bo et al studied 161 female schizophrenic patients who were evaluated at baseline after 6–8 weeks of treatment with risperidone and followed up for 52 weeks. They found that at baseline, the rate of menstrual disorders included 14.3% irregular menstruation, 6.8% oligomenorrhea, and 5% amenorrhea. At 52 weeks of follow-up, the rate of menstrual disorders was 37.9%.¹⁹ Madhusoodanan et al reported that the rate of amenorrhea among female patients treated by risperidone ranges from 1–10%.²⁰ Murke et al, reported that among 113 women receiving antipsychotics with menstrual dysfunction, 15 (30%) had amenorrhea and the rest 70% were oligomenorrhea.²¹ The mechanism of menstrual disorders, including amenorrhea, in patients using antipsychotics is thought to be due to the effect of antipsychotics on dopamine receptors in the pituitary infundibulum, causing hyperprolactinemia.²² Shettima F.B studied 209 schizophrenic patients using antipsychotics and found that the rate of increased prolactin levels was 45.9%. The rate of increased prolactin in the group using typical and atypical antipsychotics was 51.5% and 25.0%, respectively.²³ Several authors have found that risperidone is one of the antipsychotics most commonly associated with amenorrhea.²⁴ Takechi et al found that among patients treated with antipsychotics, those with menstrual disorders had serum prolactin levels 2-fold higher than those without menstrual disorders, and 70% of menstrual disorders were treated with risperidone.²⁵ In our study, the rate of risperidone use was highest, with 27 patients (45%) using it alone and 12 patients (20%) using it in combination with olanzapine (Table 2). Increased prolactin secretion due to antipsychotic use, in addition to causing menstrual disorders including amenorrhea, also leads to galactorrhea in women even when not breastfeeding, reduces sexual function, thereby reducing the quality of life of patients.²⁶ However, there have been studies that do not support a role for increased prolactin in causing amenorrhea in women taking antipsychotics.²⁷ Chen et al studied 62 women with a first psychotic episode who had not previously used antipsychotics and were followed up after 12 weeks of risperidone treatment and found that serum prolactin levels increased fourfold in women of childbearing age. But there was no difference between the amenorrhea group and the age-matched non-amenorrhea group. In contrast, low estradiol levels before treatment were a risk factor for the development of amenorrhea after 12 weeks of risperidone treatment.²⁷

Side effects on weight, metabolism, and menstrual disorders are all major causes of non-compliance with treatment in patients, increasing the rate of relapse, re-hospitalization, and difficulty in controlling psychiatric symptoms in patients. For these reasons, this study is necessary to detect unwanted effects early, have appropriate management and treatment strategies for patients using antipsychotic drugs, especially for female patients.

Strengths and Limitations

Our study is one of the first to add data on the effects of antipsychotics on weight, metabolism, and menstrual disorders, which seem to be lacking in the Vietnamese community. In addition, we want to prioritize improving the health of women, a group that is still disadvantaged in East Asian culture. Despite these strengths, our study has several limitations. First, the small sample size (n=60) may have limited the statistical power to detect significant associations in our multivariate regression analysis, which was conducted to explore factors associated with metabolic syndrome (eg, age, duration of antipsychotic use, and type of antipsychotic) but yielded no statistically significant results, leading to its exclusion from the manuscript. Second, detailed pretrial antipsychotic use history, such as exact dosages, was not uniformly available due to variability in medical records, restricting our ability to fully assess its impact. Third, the absence of longitudinal psychiatric symptom data prevented analysis of the relationship between symptom improvement and metabolic outcomes. Finally, the 12-week follow-up period was relatively short, and the use of multiple antipsychotics without uniform treatment protocols may have introduced variability. To address these limitations, we recommend future studies with larger sample sizes, longer follow-up periods, standardized antipsychotic regimens, comprehensive pretrial medication histories, and longitudinal assessments of psychiatric symptoms.

Conclusion

This study showed an association between increased weight, BMI, and amenorrhea with the use of antipsychotic medications. After 12 weeks of follow-up, the rate of components of metabolic and cardiovascular diseases also increased significantly compared to the baseline. Non-pharmacological factors, such as improved psychiatric symptoms and the structured inpatient environment (eg, regular meals), may also influence these metabolic outcomes, though our study could not assess the relationship with psychiatric symptom improvement due to the absence of longitudinal symptom data. Only one patient used clozapine, limiting our ability to evaluate its specific effects. These findings highlight the need for early detection and multidisciplinary management strategies, including endocrinology and nutrition consultations, to mitigate weight gain, metabolic disorders, and menstrual irregularities in female schizophrenic patients. Future research should incorporate larger sample sizes, longer follow-up periods, standardized antipsychotic regimens, and longitudinal assessments of psychiatric symptoms to better understand their interplay with metabolic changes and inform comprehensive treatment approaches.

Data Sharing Statement

The data that support the findings of this study are available on request from the corresponding author, upon reasonable request.

Ethics Approval

This study involved human participants and was approved by the biomedical ethics committee of Hue University of Medicine and Pharmacy (No H2023/408, issued 02/6/2024). All participants provided informed consent before participating in the study. Participation was voluntary, and patients/ relatives were fully informed about the purpose of the study. This study was carried out in compliance with the Declaration of Helsinki.

Acknowledgments

The authors wish to thank the patients and the hospital staff who participated and facilitated us in the study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This research has not received any funding.

Disclosure

The authors have no conflicts of interest to declare in this work.

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In this study, we conducted a comprehensive bibliometric analysis of global research on interferon therapy for CHB, identifying 2,035 publications from 2004 to 2025. Publication trends revealed a consistent upward trajectory. Geographical analysis identified China, the USA, and Japan as the leading contributors to CHB research, with China demonstrating the highest research output and citation impact. This dominance reflects not only the country’s substantial disease burden but also its strong investment in hepatitis B research. For instance, a meta-analysis of 3,740 studies involving over 231 million individuals documented China’s long-term reduction in HBV prevalence and regional disease heterogeneity, underscoring the country’s capacity to generate large-scale epidemiological evidence. The high research output from China correlates with its substantial national disease burden, as China still accounted for an estimated 43.3 million chronic HBV infections in 2021(3.0% prevalence), with notable variation across age groups and regions [24]. Additionally, a national economic evaluation showed that China has actively applied research insights to policy by identifying cost-effective universal screening strategies aimed at accelerating hepatitis B elimination [25]. Notably, the top three most productive institutions—Capital Medical University, Fudan University, and National Taiwan University—are all based in China, further underscoring its pivotal role in advancing the field. Key journals such as Hepatology, Journal of Hepatology, and Journal of Viral Hepatitis dominated the publication landscape. Notable publications include the widely cited “EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection,” which has accumulated 4,040 citations and remains a cornerstone in standardizing CHB care [21]. Prominent authors such as Harry L. A. Janssen, Bettina E. Hansen, and Patrick Marcellin made substantial contributions, ranking highest in productivity and citation impact. Dr. Harry L. A. Janssen, in particular, has significantly influenced the field with groundbreaking research on immune-mediated responses [26] and functional cures in CHB [27]. His work has advanced the understanding of interferon therapy’s role in achieving hepatitis B surface antigen (HBsAg) loss [28] and improving long-term clinical outcomes [29].

The top 2 cited articles in this field, both published in the Journal of Hepatology (IF = 26.8), outline key guidelines for managing hepatitis B. The 2017 article, with 4,040 citations [21], provides updated recommendations on long-term HBV suppression, treatment criteria, nucleos(t)ide analogs as first-line therapy, and the importance of ongoing monitoring to prevent disease progression and hepatocellular carcinoma. The 2012 article, which has received 2,579 citations [22], presents an earlier version of these guidelines, forming the foundation for the later updates. Together, these publications reflect the evolving clinical management strategies for chronic hepatitis B virus infection. The third most cited article, published in the New England Journal of Medicine (IF = 96.2) in 2004, has garnered 1,835 citations [23]. It highlights the efficacy of continuous lamivudine treatment in delaying disease progression, reducing hepatic decompensation and hepatocellular carcinoma risk in patients with advanced fibrosis or cirrhosis, while also addressing concerns about resistance mutations.

Research hotspots

The keyword co-occurrence analysis identified four primary research clusters in interferon therapy for CHB, each representing a distinct research focus.

Cluster 1 (Red): Immune and Molecular Mechanisms.

This cluster explores how interferon therapy modulates immune responses and influences molecular pathways. For example, studies have identified alpha-enolase as a critical regulator that suppresses interferon signaling, contributing to HBV persistence [30]. In addition, research on Schisandrin C demonstrated its ability to enhance cGAS-STING pathway activation, stimulate interferon β production, and inhibit HBV replication [31]. These findings suggest its potential as an antiviral agent [31] and provide valuable insights into the molecular underpinnings of interferon therapy.

Cluster 2 (Green): Clinical Management and Disease Progression.

This cluster focuses on the clinical application of interferon therapy, particularly in achieving sustained virological response and mitigating disease progression. Studies have shown that in HBeAg-negative CHB patients, sustained biochemical remission induced by interferon-alpha significantly improves long-term outcomes, including in individuals with cirrhosis or advanced age [32]. Moreover, IFN-α has been linked to reduced late recurrence of hepatocellular carcinoma in HCV-pure patients who adhere to treatment. However, it does not significantly prevent overall recurrence following liver resection in HCV-related cirrhosis [33].

Cluster 3 (Yellow): Combination Therapies and Treatment Strategies.

This cluster examines approaches to enhance interferon therapy effectiveness by combining it with other antiviral agents. Research has demonstrated that in NA-experienced CHB patients, combining PEG-IFN-α with NA therapy significantly enhances CD56bright natural killer cell activity. This leads to greater HBsAg reduction and improves the chance of clearance compared to NA monotherapy [34]. Additionally, sequential therapy approaches—such as bepirovirsen followed by PEG-IFN—have been shown to reduce relapse rates, particularly in patients with baseline HBsAg < 3,000 IU/mL [35]. These results underscore the potential of combination regimens to optimize treatment outcomes.

Cluster 4 (Blue): Pharmacological Advancements and Long-term Outcomes.

This cluster addresses the development of improved interferon formulations and their long-term impact on CHB management. Long-term follow-up studies suggest that PEG-IFN therapy results in favorable outcomes, with 43.4% of patients achieving a sustained off-therapy response, increased HBsAg loss rates, and no disease progression [36]. Combination therapy involving PEG-IFN-α2b and adefovir dipivoxil has shown improved virological response, though its effects on HBeAg seroconversion are limited and it is associated with increased thyroid dysfunction [37]. Further, studies reveal that PEG-IFN-α2b responders exhibit enhanced NKp30 + natural killer cell activity, which correlates with stronger antiviral cytokine production and lower HBV viral loads. Conversely, non-responders display dysfunctional NKp30 + NK cells due to elevated NKG2A expression, shedding light on variability in treatment efficacy [38].

Collectively, these research hotspots reflect a concerted effort to advance the understanding, clinical utility, and pharmacological development of interferon therapy for CHB.

Emerging topics

An analysis of citation bursts reveals a distinct progression in research priorities, transitioning from foundational studies to optimizing clinical strategies and, more recently, focusing on achieving functional cures.

From 2004 to 2013, research primarily centered on understanding the mechanisms of interferon therapy and its early clinical applications. Keywords such as “e antigen” (2004–2012), “adefovir dipivoxil” (2004–2009), and “alpha interferon” (2004–2007) highlight investigations into virological markers [39] and immune pathways [40] influenced by interferon. Concurrently, studies on “mutations” (2004–2007) and “pegylated interferon alpha-2b” (2005–2013) focused on factors affecting treatment response and improving interferon formulations [41, 42]. These early studies laid the groundwork for subsequent advancements in interferon-based CHB therapy.

Between 2014 and 2020, research priorities shifted toward optimizing interferon therapy to achieve sustained virological control. Keywords such as “virological response” (2010–2016) and “natural history” (2010–2017) illustrate efforts to understand the long-term effects of interferon treatment on disease progression [43]. The emphasis on “sustained response” (2011–2017) underscores the importance of achieving durable antiviral effects to minimize relapse [44]. Additionally, the emergence of “guidelines” (2017–2024) during this period reflects efforts to standardize evidence-based clinical practices for interferon therapy, ensuring its effective and consistent use in CHB management [45, 46].

From 2021 to 2024, research has increasingly focused on achieving a functional cure through interferon-based treatment strategies. Unlike traditional approaches aimed at viral suppression, the concept of a functional cure is defined by the sustained loss of HBsAg and undetectable HBV DNA without ongoing therapy [47]. Keywords such as “functional cure” (2021–2024), “HBsAg loss” (2021–2024), and “entecavir” (2019–2024) highlight efforts to enhance therapeutic outcomes by combining interferon with NAs such as entecavir and tenofovir [48, 49]. The emphasis on “HBsAg loss” reflects its importance as a key therapeutic milestone, as achieving this outcome is associated with long-term immune control and a reduced risk of cirrhosis and HCC [50].

Future trends

The growing focus on functional cure marks a shift in CHB treatment, aiming beyond viral suppression to sustained HBsAg loss and undetectable HBV DNA without continuous therapy. Research highlights the combination of interferon with nucleos(t)ide analogs like entecavir and tenofovir to enhance antiviral efficacy. Future efforts will refine treatment regimens by optimizing interferon dosages, timing, and combination strategies to expand the functional cure potential for a broader patient population.

These trends have clear implications for future funding priorities and clinical trial design. As “HBsAg loss” becomes a key therapeutic endpoint [50], research funding should support studies that investigate immune mechanisms underlying antigen clearance, including the roles of interferon-stimulated genes (ISGs) and cytokine pathways [51, 52, 53],. Simultaneously, predictive biomarkers are being developed to identify likely responders to interferon-based regimens [54, 55], which could inform patient stratification in future trials and improve efficiency. Clinical trials should consider adaptive designs or biomarker-guided inclusion criteria to enhance precision and reduce heterogeneity in treatment response. For instance, recent findings suggest that patients with lower baseline HBsAg levels (< 3000 IU/mL) may benefit more from sequential or combination therapies [35], indicating the importance of individualized trial arms.

The increasing interest in “entecavir” highlights its potential in combination therapies to enhance immune-mediated viral clearance. Studies have shown that adding interferon to entecavir regimens may improve sustained virological response and increase HBsAg loss, particularly in patients with high baseline antigen levels [56, 57]. Ongoing research will aim to identify optimal patient subgroups and assess long-term benefits, such as fibrosis reduction and hepatocellular carcinoma prevention.

The continuous refinement of “guidelines” from 2017 to 2024 highlights the evolving understanding and standardization of interferon therapy for CHB, closely linked to updates from major hepatology organizations, particularly the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD). The 2017 EASL guidelines introduced functional cure as a treatment goal, defined by HBsAg loss with undetectable HBV DNA, while also establishing criteria for finite nucleos(t)ide analog (NA) therapy and reaffirming interferon-based regimens as a treatment option for selected patients [21]. Subsequently, the 2018 AASLD guidelines emphasized long-term suppression of HBV DNA, advocated for careful patient selection for interferon therapy, and encouraged more individualized treatment approaches to optimize therapeutic outcomes [58].

Recent updates, particularly the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference, have further refined treatment endpoints, reinforcing interferon’s role as a potential functional cure strategy [50]. Emerging clinical trial data suggest that interferon-based combination therapies, especially when paired with antiviral agents, could enhance treatment efficacy, influencing the direction of future guideline revisions. Additionally, real-world evidence (RWE) is expected to be incorporated into upcoming guidelines, refining patient eligibility criteria, treatment duration, and combination regimens to ensure more personalized and effective therapeutic strategies. Addressing global equity and accessibility is also a growing priority, ensuring that both interferon and antiviral therapies remain available in resource-limited settings. Furthermore, advances in biomarkers and host immune response assessments are paving the way for more precision-based treatment decisions. As interest in interferon-based combination strategies continues to grow, future guidelines may undergo further adaptations to integrate novel therapeutic insights. These continuous updates reflect a dynamic research landscape and an ongoing commitment to optimizing CHB management, ensuring that interferon therapy remains a viable and strategically positioned option for selected patient populations.

Strengths and limitations

This bibliometric analysis provides a comprehensive overview of global research trends, key contributing countries, and thematic focuses in interferon therapy for chronic hepatitis B (CHB) from 2004 to 2025. By leveraging analytical tools such as VOSviewer, CiteSpace, and R-bibliometrix, the study identifies historical trajectories and emerging directions in immune mechanisms, therapeutic strategies, and pharmacological innovations.

Several limitations, however, should be acknowledged:

First, citation-based metrics may not accurately capture the clinical significance or translational impact of research. Highly cited studies are not necessarily those with the greatest real-world applicability or influence on clinical practice.

Second, the analysis was restricted to publications indexed in the Web of Science Core Collection, which predominantly includes English-language journals. While this enhances consistency and data quality, it may introduce language and regional bias by excluding relevant studies published in non-English languages or local journals. This is particularly important in the context of CHB, which has high prevalence in regions such as Asia and Africa, where impactful research may appear in local-language publications.

Third, reliance on a single bibliographic database may limit the breadth and diversity of the dataset. Different databases—such as Scopus, PubMed, and Embase—offer varying coverage of journals and document types. As a result, some relevant literature not indexed in Web of Science may have been omitted. Future bibliometric studies could improve coverage and inclusiveness by integrating multiple, multilingual databases.

Fourth, citation counts were not normalized by publication age. Older articles naturally accumulate more citations over time, which may bias the identification of “highly influential” publications toward earlier studies. Future work may consider applying age-normalized citation metrics (e.g., citations per year) or field-weighted indicators to more accurately assess comparative impact across time.

Fifth, this study did not explore potential authorship biases related to gender, institutional affiliation, or regional origin. Such dimensions are increasingly recognized as important factors influencing scholarly visibility, resource distribution, and collaborative networks. For instance, researchers from high-income countries or prestigious institutions may have greater access to funding, networks, and publication opportunities, which can skew citation and authorship patterns. Similarly, underrepresentation of women or scholars from low- and middle-income regions in leading authorship roles may reflect broader systemic inequities. Future bibliometric studies should incorporate author-level metadata where available and consider equity-focused indicators to better understand and address such disparities.

Sixth, the study period was limited to publications from January 1, 2004, to January 8, 2025. This time frame was selected to capture developments following the introduction and widespread clinical adoption of pegylated interferon, which marked a significant therapeutic shift in CHB management. However, we acknowledge that interferon therapy has been used and studied since the early 1980s, and foundational research from earlier decades played a critical role in shaping current understanding and treatment paradigms. Due to database limitations and to maintain relevance to modern clinical practice, earlier literature was not included in the present analysis. Future bibliometric studies aiming for a more historical perspective may benefit from extending the time frame to encompass these seminal contributions.

Finally, while bibliometric indicators offer quantitative insights into research productivity and collaboration, they do not fully reflect clinical outcomes or societal impact. Incorporating alternative metrics—such as expert evaluations, implementation outcomes, and health system impact—would provide a more comprehensive understanding of the influence and utility of interferon therapy research. Future work that combines bibliometric data with clinical effectiveness studies may offer a more holistic assessment of progress in CHB management.