Retrospective Analysis of Therapeutic Drug Monitoring Results for Risperidone from 2022 to 2024

LIANG Lingjun¹, ZHANG Jun², CHEN Jianhui¹, GAO Yongshuang¹*

¹Department of Pharmacy, Zhongshan Third People's Hospital, Zhongshan 528400, China
²The Second People's Hospital of Hekou District, Dongying 257000, China

Corresponding author: GAO Yongshuang, Chief pharmacist, E-mail: 409632800@qq.com

Abstract

Background: Risperidone, as an antipsychotic medication, is widely used in the treatment of schizophrenia and other mental disorders. Although therapeutic drug monitoring (TDM) of risperidone plasma concentrations has been implemented for many years both domestically and internationally, consensus has not been reached regarding the influence of gender and age differences on plasma concentration results.

Objective: By collecting risperidone TDM data, this study analyzed the distribution of risperidone TDM across different therapeutic windows and the effects on plasma concentrations among patients with different visit types, genders, and ages, to provide medication references for patients with schizophrenia and other mental disorders taking risperidone.

Methods: Using the hospital information retrieval system, we collected basic information including age, gender, plasma concentration data, monitoring frequency, and number of monitoring cases for outpatients and inpatients who underwent risperidone TDM at Zhongshan Third People's Hospital from 2022 to 2024. According to the risperidone therapeutic window range recommended by the 2017 AGNP Consensus Guidelines for Therapeutic Drug Monitoring of the Association for Neuropsychopharmacology and Pharmacopsychiatry (<20 ng/mL as below therapeutic window, 20–60 ng/mL as within therapeutic window, and >60 ng/mL as above therapeutic window), we conducted categorical statistics to compare the distribution of risperidone TDM across different therapeutic windows and its influence on plasma concentrations among patients of different years, visit types, age groups, and genders. Data analysis was performed using SPSS 29.0, and graphs were created using Origin Pro 2021.

Results: This study included 2,583 patients with a total of 4,879 monitoring sessions, comprising 1,738 sessions for females and 3,141 sessions for males. The number of risperidone TDM sessions increased annually, with a 28.61% increase in 2023 compared to 2022 and a 71.31% increase in 2024 compared to 2022. Among the 2,583 monitored patients, the proportion of outpatients receiving one monitoring session was higher than that of inpatients (χ² = 115.48, P < 0.001), while the proportion of inpatients receiving two or more than three monitoring sessions was higher than that of outpatients (χ² = 7.22, P = 0.007; χ² = 102.68, P < 0.001). No statistically significant difference was found in risperidone plasma concentrations between outpatients and inpatients (Z = -1.254, P = 0.210). Male patients had lower risperidone plasma concentrations than female patients (Z = -11.54, P < 0.001), and significant differences were observed in risperidone plasma concentrations among different age groups (H = 36.56, P < 0.001). From 2022 to 2024, risperidone TDM was within the therapeutic window in 3,445 sessions (70.61%), below the therapeutic window in 471 sessions (9.65%), and above the therapeutic window in 963 sessions (19.74%). The proportion of monitoring within the therapeutic window was significantly higher than the other two categories (χ² = 3,772.19, 2,548.73, P < 0.001). Significant differences were observed in monitored plasma concentrations across the three categories (below, within, and above therapeutic window) from 2022 to 2024 (H = 1,465.03, P < 0.001). The distribution proportions of risperidone TDM across different therapeutic windows showed statistically significant differences among patients of different years, age groups, and genders (P < 0.001). The monitored plasma concentrations of risperidone TDM in male, female, and overall samples were 37.4 (26.7, 52.3) ng/mL, 45.3 (32.4, 60.9) ng/mL, and 40.2 (28.6, 55.6) ng/mL, respectively—all within the 20–60 ng/mL range, consistent with the AGNP consensus-recommended risperidone therapeutic window (20–60 ng/mL).

Conclusion: In clinical practice, the influence of gender and age differences on risperidone TDM should be considered to implement individualized risperidone treatment, thereby increasing the proportion of plasma concentrations within the therapeutic window. Simultaneously, greater emphasis should be placed on the application of TDM in both outpatient and inpatient treatment to ensure safe and effective clinical medication use.

Keywords: risperidone; therapeutic drug monitoring; plasma concentration; schizophrenia; therapeutic window; retrospective analysis

Introduction

Risperidone is a first-line antipsychotic medication used for the treatment of schizophrenia and other mental disorders. Research indicates that risperidone plasma concentrations are influenced by factors including dosage, patient age, gender, concomitant medications, pathological conditions, and cytochrome P450 (CYP) 2D6 genetic polymorphisms, and that clinical efficacy and adverse reactions are correlated with plasma concentrations. Therefore, implementing therapeutic drug monitoring (TDM) for patients taking risperidone may achieve an optimal balance between clinical efficacy and adverse reaction risk.

Currently, TDM has been widely implemented across multiple drug classes, including psychiatric medications, cardiovascular drugs, immunosuppressants, antineoplastic agents, and antibiotics. As a branch of clinical pharmacy, TDM quantitatively analyzes drug exposure in the human body using quantitative analytical techniques, dynamically adjusting drug dosage or related drug combinations based on therapeutic ranges, clinical efficacy, and tolerability to develop precise, individualized medication regimens for patients. In clinical practice, populations with clear indications for implementing risperidone TDM include patients requiring long-term risperidone treatment, those with narrow therapeutic windows, special populations (elderly, pregnant women, children, and those with hepatic or renal insufficiency), and patients with large inter-individual pharmacodynamic and pharmacokinetic variability. TDM maximizes clinical medication safety and efficacy while reducing the incidence of potential adverse reactions. Additionally, since TDM quantitatively monitors drug exposure in the body and provides timely information on patient medication adherence, it serves as an objective means of assessing patient compliance. According to the 2017 AGNP Consensus Guidelines for Therapeutic Drug Monitoring of the Association for Neuropsychopharmacology and Pharmacopsychiatry (hereinafter referred to as the AGNP Consensus), TDM for risperidone is strongly recommended in clinical practice.

Although risperidone plasma concentrations have been monitored through TDM technology for many years both domestically and internationally, consensus has not been reached regarding the influence of gender and age differences on concentration results. CASTBERG et al. found that age and gender may affect risperidone metabolism in vivo, leading to different plasma concentrations in patients receiving the same dose. However, other studies have shown no statistically significant differences in the metabolite-to-parent drug plasma concentration ratios of risperidone between male and female patients in the same age group. Based on risperidone TDM results, this study retrospectively analyzed the overall clinical situation of risperidone TDM at Zhongshan Third People's Hospital, explored the effects of different age groups and genders on TDM results, and identified potential influencing factors to provide references for individualized risperidone medication.

Methods

1.1 Basic Information

Through the information system of Zhongshan Third People's Hospital, we retrospectively collected basic information for outpatients and inpatients who took risperidone and underwent plasma concentration monitoring from 2022 to 2024, including patient age, gender, number of monitoring cases, monitoring frequency, and original TDM data. This study was approved by the Ethics Committee of Zhongshan Third People's Hospital. Due to the use of anonymous retrospective data with minimal risk, informed consent was waived.

1.2 Sample Collection

Blood samples were collected from patients receiving risperidone treatment in outpatient or inpatient settings who met the indications for psychiatric TDM. Inclusion criteria: (1) patients had used oral risperidone formulations and reached steady-state plasma concentration after continuous medication; (2) blood collection occurred in the morning before medication administration. Exclusion criteria: (1) patients who had used drugs affecting risperidone metabolic activity (fluoxetine, duloxetine, paroxetine) before sample collection; (2) pregnant and lactating women.

1.3 Sample Processing

Collected blood samples were centrifuged at 4,000 r/min for 5 minutes to separate plasma. Using a pipette, 200 µL of plasma was transferred to a 1.5 mL Eppendorf microcentrifuge tube, and 500 µL of acetonitrile was added. The mixture was vortexed for 40 seconds, then centrifuged at 14,000 r/min for 10 minutes at 4°C. After centrifugation, the supernatant was transferred to a 96-well plate using a pipette for quantitative detection using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

1.4 Risperidone Plasma Concentration Determination

Risperidone plasma concentrations were monitored and analyzed using an established HPLC-MS/MS method in our laboratory. The system consisted of a Shimadzu 8040 LC-MS/MS instrument equipped with a DGU-20A3R automatic degasser, LC-20A binary high-pressure pump, SIL-20AHT-UFLC autosampler, and CTO-20A column oven. The quantitative determination method for risperidone plasma concentration analysis complied with the 2020 edition of the Chinese Pharmacopoeia method validation, examining specificity, accuracy, precision, sensitivity, linear range, matrix effects, and stability—all of which met requirements, confirming suitability for risperidone plasma concentration monitoring. Calibrators and quality control samples for risperidone plasma concentration quantification were controllable, with quality control performed according to our established HPLC-MS/MS method.

1.5 Recommended Therapeutic Window Concentration Reference Range

Based on the therapeutic window concentration reference range recommended by the AGNP Consensus (<20 ng/mL as below therapeutic window, 20–60 ng/mL as within therapeutic window, and >60 ng/mL as above therapeutic window), with a laboratory alert value of 120 ng/mL, risperidone TDM data were statistically analyzed and distribution proportions were calculated.

1.6 Statistical Analysis

This study used Origin Pro 2021 for graph creation and SPSS 29.0 for statistical analysis. Normally distributed measurement data were expressed as (x̄ ± s) and analyzed using independent samples t-test for two-group comparisons and one-way ANOVA for multi-group comparisons. Non-normally distributed measurement data were expressed as M(P₂₅, P₇₅) and analyzed using Mann-Whitney U test for two-group comparisons and Kruskal-Wallis H test for multi-group comparisons. Count data were expressed as relative numbers and analyzed using χ² test for inter-group comparisons. P < 0.05 was considered statistically significant.

Results

2.1 General Monitoring Situation

From 2022 to 2024, 2,583 patients underwent risperidone TDM with 4,879 monitoring sessions, including 3,141 sessions for male patients (64.38%) and 1,738 sessions for female patients (35.62%). Patient ages ranged from 11 to 92 years. The number of monitoring sessions increased annually, with a 28.61% increase in 2023 compared to 2022 and a 71.31% increase in 2024 compared to 2022. Among the 2,583 monitored patients, 363 were outpatients with 404 monitoring sessions (8.28%), and 2,220 were inpatients with 4,475 monitoring sessions (91.72%). The proportion of outpatients receiving one monitoring session was significantly higher than that of inpatients (χ² = 115.48, P < 0.001), while the proportion of inpatients receiving two or more than three monitoring sessions was higher than that of outpatients (χ² = 7.22, P = 0.007; χ² = 102.68, P < 0.001) [TABLE:1].

2.2 Effects of Different Visit Types, Gender, and Age on Risperidone Plasma Concentration

No statistically significant difference was found in risperidone plasma concentrations between outpatients and inpatients (P > 0.05). Male patients had significantly lower risperidone plasma concentrations than female patients (P < 0.001). Significant differences were observed in risperidone plasma concentrations among different age groups (P < 0.05), with patients aged 18–60 years having higher concentrations than those <18 years and >60 years (P < 0.001) [TABLE:2].

2.3 Distribution of Risperidone TDM Across Different Therapeutic Windows by Year

From 2022 to 2024, risperidone TDM was within the therapeutic window in 3,445 sessions (70.61%), below the therapeutic window in 471 sessions (9.65%), and above the therapeutic window in 963 sessions (19.74%). The proportion of monitoring within the therapeutic window was significantly higher than the other two categories (χ² = 3,772.19, 2,548.73, P < 0.001). The distribution of risperidone TDM across therapeutic windows differed significantly between outpatients and inpatients, with outpatients having higher proportions below and above the therapeutic window but a lower proportion within the therapeutic window compared to inpatients (χ² = 16.37, 4.50, 20.04, P < 0.001, P = 0.034, P < 0.001). These differences were consistent across individual years [TABLE:3].

2.4 Distribution of Risperidone TDM Across Different Therapeutic Windows by Age Group

Patients were grouped by age: <18 years, 18–60 years, and >60 years. The proportions of monitoring within the therapeutic window were 66.67%, 70.87%, and 69.92% respectively, with all groups showing therapeutic window as the primary category. However, the distribution across therapeutic windows differed significantly among age groups (χ² = 43.182, P < 0.001) [TABLE:4].

2.5 Distribution of Risperidone TDM Across Different Therapeutic Windows by Gender

Male and female patients showed monitoring proportions within the therapeutic window of 72.11% and 67.89% respectively, with both groups primarily distributed within the therapeutic window. However, the distribution across therapeutic windows differed significantly between genders (χ² = 85.644, P < 0.001) [TABLE:5].

2.6 Comparison of Monitored Plasma Concentrations with AGNP Consensus-Recommended Therapeutic Window

The monitored plasma concentrations of risperidone TDM in male, female, and overall samples were 37.4 (26.7, 52.3) ng/mL, 45.3 (32.4, 60.9) ng/mL, and 40.2 (28.6, 55.6) ng/mL, respectively—all within the 20–60 ng/mL range, consistent with the AGNP consensus-recommended risperidone therapeutic window (20–60 ng/mL) and demonstrating good concordance [FIGURE:1].

Discussion

Risperidone, as an antipsychotic medication, is widely used in psychiatric clinical practice for the treatment of schizophrenia and other mental disorders such as bipolar disorder and autism spectrum disorder-related symptoms. To balance clinical efficacy and tolerability, risperidone plasma concentrations are typically maintained within the therapeutic window of 20–60 ng/mL. When plasma concentration exceeds 60 ng/mL, the incidence of adverse drug reactions increases significantly with rising concentration, while concentrations below 20 ng/mL may result in suboptimal therapeutic efficacy. Therefore, implementing TDM for patients taking risperidone is crucial for improving medication safety, efficacy, cost-effectiveness, and rationality. Previous studies have shown that factors such as gender and age can affect risperidone plasma concentrations, though consensus on these effects has not been reached. This retrospective study collected risperidone TDM data from 2022 to 2024 to analyze the distribution of risperidone TDM and the effects of different age groups and genders on plasma concentrations, providing references for individualized treatment of patients with schizophrenia and other mental disorders during long-term therapy.

Our results showed that among 2,583 patients monitored from 2022 to 2024, 1,709 patients (66.16%) had only one TDM session. Among 363 outpatients, 330 (90.91%) had only one monitoring session. The proportion of patients receiving a single TDM session was significantly higher among outpatients than inpatients, suggesting that empirical medication use is common in psychiatric practice, particularly in outpatient settings. Additionally, the proportion of risperidone TDM within the therapeutic window was significantly lower for outpatients than inpatients (P < 0.001), with significant differences in plasma concentrations between these groups (P < 0.05), indicating poorer medication adherence among outpatients compared to inpatients. Outpatients may exhibit poor compliance through irregular medication intake, missed doses, or unauthorized discontinuation after discharge. Studies have shown that medication adherence in patients with schizophrenia and other mental disorders is closely related to disease recovery, deterioration, and relapse risk. As an emerging monitoring technology, TDM can identify medication adherence issues based on plasma concentration results, providing guidance for improving clinical efficacy. Our results also showed that the proportion of risperidone TDM within the therapeutic window increased by 3.70% in 2024 compared to 2022 and by 0.62% compared to 2023, indicating improved responsiveness to TDM in individualized psychiatric treatment. In summary, TDM implementation should be strengthened for outpatients to assess medication adherence based on plasma concentration results, promptly identify medication problems, and reduce disease recurrence due to compliance issues. For inpatients, TDM should be used to dynamically adjust medication dosage or drug combinations based on plasma concentration results, clinical efficacy, and tolerability, thereby maximizing therapeutic effects, minimizing adverse reactions, and reducing hospitalization duration.

Regarding gender, our data analysis showed that female patients had higher risperidone plasma concentrations [45.3 (32.4, 60.9) ng/mL] than male patients [37.4 (26.7, 52.3) ng/mL], consistent with the findings of GUO et al. Risperidone is primarily metabolized by cytochrome P450-2D6 enzyme (CYP2D6) to its active metabolite 9-hydroxyrisperidone (9-OH-RIS). CYP2D6 exhibits genetic polymorphism, and enzyme activity differs between genders, potentially leading to differences in risperidone plasma concentrations. Additionally, women generally have lower blood volume, smaller body size, and lower body weight than men, which may result in higher drug exposure. Given the lack of large-scale cohort studies on the correlation between risperidone plasma concentrations and Chinese populations, further large-sample studies are needed to investigate this influencing factor and improve gender-specific guidance for risperidone use.

Regarding age, CYP2D6 metabolic capacity may decrease with age, though previous studies have yielded controversial results about age effects on CYP2D6 activity. Our study found that elderly patients had significantly lower risperidone plasma concentrations than middle-aged and young adults, contradicting previous research showing higher concentrations in elderly patients. We hypothesize this may be due to correlations between plasma concentrations and administered doses in our elderly population, though this requires further investigation as our study did not examine the relationship between plasma concentration and dosage.

Our analysis of 4,879 risperidone TDM sessions reflects the current status of risperidone TDM. The AGNP Consensus suggests that when effective therapeutic data are unavailable, an initial "therapeutic reference range" can be established using steady-state trough concentrations (x̄ ± s). However, Hiemke et al. demonstrated that using M(P₂₅, P₇₅) shows higher consistency with AGNP Consensus recommendations than (x̄ ± s). Our results showed that risperidone plasma concentrations in male, female, and overall samples all fell within the 20–60 ng/mL range, consistent with AGNP Consensus recommendations. Additionally, 70.61% of risperidone TDM sessions fell within the reference range recommended by the AGNP expert panel, while 29.39% fell outside this range. Based on the 95% medical reference range rule, our institution's actual clinical reference range was determined to be 12.74–97.53 ng/mL, which is broader than the AGNP Consensus-recommended range. Therefore, although most of our overall sample fell within the AGNP-recommended concentration range, our institution's actual clinical concentration range was wider.

Limitations

This study has several limitations: (1) The analysis of differences in risperidone TDM results lacked integration with clinical efficacy and tolerability assessments; (2) When analyzing the effects of different visit types, genders, and ages on TDM results, factors such as dosage, formulation, concomitant medications, comorbidities, and metabolic gene polymorphisms were not included in the analysis; (3) In the age group analysis, sample sizes for the <18 years and >60 years groups were relatively small compared to the 18–60 years group, potentially introducing bias; (4) This study only included data from our institution and may not represent TDM distribution patterns in other regions of China. Future research should expand sample sizes for more in-depth investigation of relevant influencing factors.

Conclusion

In summary, by analyzing risperidone TDM results from 2022 to 2024, we found that age and gender affect patient plasma concentrations, with female patients showing higher TDM-monitored plasma concentrations than male patients. Additionally, most of our institution's risperidone TDM-monitored plasma concentrations fell within the AGNP-recommended range, though our actual clinical concentration range was broader. Therefore, in clinical practice, greater emphasis should be placed on therapeutic drug monitoring to optimize treatment plans based on plasma concentrations, which holds significance for evaluating patient medication adherence, developing individualized dosing regimens, improving responsiveness, and reducing adverse reactions.

Author Contributions: LIANG Lingjun was responsible for conceptualization, methodology design, and manuscript writing; ZHANG Jun was responsible for standardization and revision; CHEN Jianhui was responsible for data collection, classification, statistical analysis, and figure creation; GAO Yongshuang was responsible for quality review and supervision.

Conflict of Interest: None declared.

ORCID IDs: LIANG Lingjun https://orcid.org/0009-0004-7668-7301; GAO Yongshuang https://orcid.org/0000-0003-0977-5948

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Received: June 20, 2025; Revised: August 10, 2025
Edited by: KANG Yanhui