Relationship between plasma risperidone concentrations and clinical features in chronic schizophrenic patients in China

BACKGROUND Prior studies have noted great variability in the plasma levels of risperidone(RIS).Plasma concentrations of RIS and its active moiety are highly variable and depend on absorption,metabolism,and other predictors of metabolic dysregulation;however,these factors are poorly understood and the association between metabolic change and change in psychopathology is uncertain.AIM To ascertain the characteristics of chronic schizophrenic patients treated with RIS,and to assess their relationship with plasma RIS levels.METHODS This was a descriptive cross-sectional study of 50 patients with a diagnosis of schizophrenic psychosis treated with RIS in a psychiatric service.The plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone were determined by high performance liquid chromatography.The patients’demographic and clinical characteristics,and psychopathologies were assessed,and the associations between clinical variables and plasma levels of RIS were explored.RESULTS Male patients received higher doses of RIS than female ones,but plasma concentrations of RIS and risperidone+9-hydroxyrisperidone(active moiety)were higher in female patients.Age and the mean scores of the general psychopathology subscale of the Positive and Negative Syndrome Scale(PANSS)were significantly positively correlated with plasma concentrations of risperidone+9-hydroxyrisperidone adjusted for weight and dose in all 50 subjects.In male subjects,we found a statistically significant positive correlation between the concentrations of risperidone+9-hydroxyrisperidone in plasma/(dose×kg)and age,mean PANSS negative subscale scores,mean PANSS general psychopathology subscale scores,and mean PANSS total scores.CONCLUSION Long-term use of RIS should be closely monitored in older patients and females to minimize the risk of high concentrations which could induce side effects.

Risperidone治疗精神分裂症的临床研究

本文介绍新药Ｒｉｓｐｅｒｉｄｏｎｅ治疗精神分裂症的临床研究进展

~1H and ^(13)C NMR Assignments for Amlodipine and Risperidone

Aim To investigate the NMR spectroscopy of amlodipine and risperidone.Methods 1D NMR and 2D NMR experimental techniques of gCOSY, gHSQC and gHMBC were wsed. Results Theassignments of the ~1H and ^(13) C NMR data for the two drugs were performed and confirmed by theevidence of J_(HF) and J_(CF). Conclusion The structures of amlodipine and risperidone wereconfirmed by careful analysis of regular 1D and 2D NMR spectroscopy.

新药Risperidone治疗精神分裂症的临床研究

报告了新型非典型抗精神病药物Risperidone治疗精神分裂症的临床研究结果，通过自身对照及与氟哌啶醇、奋乃静、氯氮平对照研究发现，Risperidone对阴、阳性症状有效，尤对阴性症状效果好，而且很少有锥外系副反应，是一种很有前途的抗精神病药物。

Determination of risperidone in human plasma by HPLC-MS/MS and its application to a pharmacokinetic study in Chinese volunteers

This study presents a rapid, specific and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay for determination of risperidone (RIS) in human serum using paroxetine as an internal standard (IS). An Alltima-C18 column (2.1 mm×100 mm, 3 μm) and a mobile phase consisting of 0.1% formic acid-acetonitrile (40:60, v/v) were used for separation. The analysis was performed by selected reaction monitoring (SRM) method, and the peak area of the m/z 411.3→191.1 transition for RIS was measured versus that of the m/z 330.1→192.1 transition for IS to generate the standard curves. The assay linearity of RIS was confirmed over the range 0.25～50.00 ng/ml and the limit of quantitation was 0.05 ng/ml. The linear range corresponds well with the serum concentrations of the analytes obtained in clinical pharmacokinetic studies. Intraday and interday relative standard deviations were 1.85%～9.09% and 1.56%～4.38%, respectively. The recovery of RIS from serum was in the range of 70.20%～84.50%. The method was successfully applied to investigate the bioequivalence between two kinds of tablets (test versus reference products) in 18 healthy male Chinese volunteers. The result suggests that two formulations are bioequivalent.

Platelet cytochrome c-oxidase activity in patients with acute schizophrenia in the course of their treatment with risperidone

Objectives: Testing a hypothesis, that platelet cytochrome c-oxidase (COX) activities in patients with paranoid schizophrenia, acute episode, may be linked to dynamics of their clinical patterns and quality of cognitive functioning under antipsychotic treatment. Methods: Psychopatho-logical (PANSS, NSA-16) and cognitive assess-ments;platelet COX enzymatic activity determination, post-hoc nonparametric statistical analysis. Results: Psychopathological and cognitive assessments were done and blood was sampled in patients before (at baseline) and after treatment with risperidone. Following regu- larities were found after the treatment of patients: Significant elevation of COX, wherein the higher was COX at baseline, the more prominent was decrease in PANSSneg and NSA rates;significant negative correlation between COX and executive time in cognitive tests. When the patient group was divided by median of COX at baseline into two subgroups (greater or equal median, and 20% was assigned to the first subgroup;significantly larger amount of patients with PANSSneg by <20% was assigned to the second group. Conclusions: Therapy with risperidone seems to be more effective for patients with higher COX activity at baseline, but this fact requires further study.

Different effects of paliperidone and risperidone therapy on blood lipid and Hcy metabolism as well as endocrine hormones in patients with schizophrenia

Objective: To explore the different effects of paliperidone and risperidone therapy on blood lipid and Hcy metabolism as well as endocrine hormones in patients with schizophrenia. Methods: A total of 118 patients with schizophrenia who were treated in the hospital between December 2014 and February 2017 were collected as the research subjects and divided into control group and study group by random number table, each group with 59 cases. Control group received risperidone therapy, observation group received paliperidone therapy, and the differences in the levels of blood lipid indexes, Hcy metabolism indexes and endocrine hormones were compared between the two groups before and after treatment. Results:There was no statistically significant difference in the levels of blood lipid indexes, Hcy and endocrine hormones between the two groups before treatment. After treatment, lipid indexes TG and TC levels in peripheral blood of study group were lower than those of control group while HDL-C content was higher than that of control group;Hcy level in serum of study group was lower than that of control group;endocrine hormones FT3, FT4, T and E2 levels in serum of study group were higher than those of control group. Conclusion: paliperidone therapy for schizophrenia can be more effective than risperidone in regulating blood lipid metabolism, Hcy metabolism and endocrine hormones.

Correlation of hair risperidone concentration and serum level among patients with schizophrenia

Background Risperidone (RSP) has a rapid onset in vivo, low dosage and high plasma protein binding rate, therefore therapeutic drug monitoring (TDM) is needed to ensure safety in clinical treatment. However, compared with blood, hair is non-invasive, safe, non-infectious and easy to transport and store. Aims This study aims to investigate the correlations among the drug concentrations of RSP in hair and serum, which provides an experimental basis to explore hair as a novel biomaterial to meet the needs of clinical detection. Methods 34 patients with schizophrenia treated with RSP for more than 3 months were enrolled in this study. About 1 cm section of hair near the scalp was taken from the subjects, pretreated and detected by liquid chromatography-mass spectrometry. A correlation analysis was conducted among the drug concentrations in hair, the serum concentrations and the daily dosage. The data were analysed usi叩 SPSS 20.0 software. Results There was significant correlation between the hair concentration of RSP (two-tailed test, r=0.440, p=0.009) with the serum concentration of RSP, and the hair concentration of 9-hydroxyrisperidone (9-HR) with the serum concentration of 9-HR had no significant correlation (two-tailed test, r=-0.217, p=0.217);the total concentration of the RSP and 9-HR had no significant correlation between hair and serum (r=0.227, p=0.196). The dosage had no statistically significant correlation with the concentration of RSP in hair (r=0.207, p=0.241), 9-HR in hair (r=-0.194, p=0.271) and the total concentration of RSP and 9-HR in hair (r=0.188, p=0.288). There was no statistical correlation between the dosage and the concentration of RSP in serum (r=-0.059, p=0.741), but significant correlation between the dosage and 9-HR in serum (r=0.581 p<0.001) was found, and the correlation between the dosage and the total concentration of the two drugs RSP and 9-HR in serum was also significant (r=0.437, p=0.01). Conclusion The correlation analysis showed that the concentration of RSP in hair was statistically significant with the serum RSP concentration. In this study, we provided some experimental basis for hair as a new biomaterial to monitor the therapeutic drug concentration.

Effect of genetic polymorphisms on the interplay of P-glycoprotein transporter and cytochrome P450 enzymes: Pharmacokinetics of risperidone

Inter-individual variability in oral drug efficacy and toxicity is commonly observed in all therapeutic areas.Importantly,interindividual variability in drug uptake and metabolism can result in poor drug response,adverse drug reactions,or unfavorable drug–drug interaction.One of the common causes of individual variations in drug response is genetic variation of drug transporters and metabolizing enzymes[1,2].We focus on the interplay between efflux transporter(ATP-binding cassette,subfamily B(MDR/TAP),member 1/ABCB1)and cytochrome P450s according to genetic polymorphism[3].The objective of this lecture is to investigate the combined influence of genetic polymorphisms in ABCB1 and CYP2D6 genes on risperidone pharmacokinetics[4].

Optimal needle insertion length for intramuscular injection of risperidone long-acting injectable (RLAI)

Risperidone long-acting injectable (RLAI) is approved for the treatment of schizophrenia in many countries. The suggested site is the gluteal muscle with a needle length of two inches (50 mm) in Japan, which is longer than the ordinarily used needle for intramuscular injections. The aim of this study was to determine the optimal needle insertion length for accurate delivery of RLAI procedure among subjects who have normal body mass index (BMI: 18 to 25) and high BMI (>25). Thirty-seven patients with schizophrenia were administered RLAI intramuscularly into the dorsogluteal muscle. The standard procedure required inserting 80% of the two inch needle. By using data collected by ultrasonography, the findings confirmed that the median needle insertion lengths for subjects with normal and high BMI were 39.0 and 45.5 mm, respectively. To deliver RLAI effectively and safely, the authors strongly recommend that a specialized needle be used that is “marked” at the 40 mm point from the tip of the needle to the base. In this way regardless of subcutaneous fat content, the RLAI can be safely delivered into the muscle without causing untoward or side effects.

Effect of Risperidone and Fluoxetine on the Movement and Neurochemical Changes of Zebrafish

Brain developmental disorders in humans, including Autism Spectrum Disorders (ASD) and Down’s syndrome, have been linked to increased serotonin levels. This work was designed to study changes in serotonin levels in the early stages of development with two classes of antipsychotic drugs: Risperidone, a drug that blocks serotonin and dopamine receptors, and fluoxetine, a serotonin reuptake inhibitor. The use of antipsychotic drugs is a solid choice to study the decrease and increase of these neurotransmitters and their influence on development. The study of these parameters will give an idea of the effects of serotonin in early developmental stages. To this end, we examined the effects of risperidone and fluoxetine on the locomotor activity, heart rate and brain development of zebrafish larvae. Our results showed that in larvae exposed to fluoxetine alone, swimming was significantly increased at 9 dpf (days post-fertilization). Erratic and abnormal movements were observed suggesting a toxic effect of fluoxetine. No erratic swimming was observed in larvae treated with fluoxetine plus risperidone. Both drugs presented morphological changes in dopaminergic neurons and mononeurons. Exposure to fluoxetine plus risperidone indicated possible reversal effects. Studies in zebrafish allow obtaining new insights into the side effects of these drugs as well as into the brain control of locomotor activity. Testing several drug-induced changes in behavior and serotonin levels is one of the experimental approaches for screening a new therapeutically relevant compound, and thus, merits further research.

A meta-analysis of phlegm-resolving Chinese medicine combined with risperidone for treatment of schizophrenia

Objective:The efficacy and occurrence of adverse reactions of prescriptions containing phlegm-resolving Chinese medicine combined with risperidone in the treatment of schizophrenia were retrospectively studied by means of meta-analysis.Methods:A variety of different Chinese and English databases were searched from January 1,2000 to May 1,2020.Review Manager 5.3 software was used to evaluate the methodological quality of the included studies.The positive and negative symptom scale(PANSS)was used as the evaluation standard to analyze the total scores,positive scores,negative scores and general psychopathological scores,clinical efficacy and safety of prescriptions containing phlegmresolving Chinese medicine combined with risperidone of schizophrenia.The heterogeneity test and sensitivity analysis were also carried out by Review Manager 5.3,and the potential publication bias was analyzed by"funnel plot".Results:A total of 1515 patients were included in 15 studies.Compared with control group of risperidone alone,the total PANSS scale score,positive symptom score,negative symptom score and general psychopathological score of the treatment group of phlegm-resolving Chinese medicine combined with risperidone were all lower than those of the control group(P=0.01,MD=-6.35,95%CI[-11.29,-1.40]),(P=0.04,MD=-1.42,95%CI[-2.74,-0.09]),(P<0.01,MD=-2.16,95%CI[-3.41,-0.91]),and(P<0.01,MD=-3.80,95%CI[-6.37,-1.24]),the clinical efficacy of phlegm-resolving Chinese medicine combined with risperidone treatment group on schizophrenia was better than that of the control group[P<0.01,RR=1.09,95%CI(1.05-1.13)].The incidence of adverse reactions was reduced(P=0.02,RR=0.56,95%CI[0.34-0.93]).Conclusion:The combination of prescriptions containing phlegm-resolving Chinese medicine and risperidone can effectively improve the efficacy of patients with schizophrenia and reduce the occurrence of adverse drug reactions compared with risperidone alone.

Co-Administration of Risperidone and Sodium Valproate Causing Bilateral Chronic Exertional Lower Leg Compartment Syndrome

We present the case of a 24-year-old man, who was a keen runner, developing chronic bilateral lower leg compartment syndrome following co-administration of Risperidone and Sodium Valproate. Having had failed medical and physical therapies, he underwent surgical decompression of his more problematic left lower leg compartments. In the interval between sequential fasciotomies, control of his psychiatric symptoms allowed the dose of his Risperidone to be reduced, resulting in a greater exercise tolerance. Ultimately he no longer required the contra-lateral lower leg compartments to be decompressed surgically. He had returned to his original level of activity with no further psychotic episodes.

Intramuscular Diffusion Status of Risperidone and Aripiprazole Long Acting Injectable (LAI) by Ultrasonography

The aim of this study was to consider the characteristics of intramuscular diffusion status of risperidone and aripiprazole long acting injectable (LAI) by ultrasonography. Subjects were 40 adult subjects diagnosed with schizophrenia and treated with LAI [32 patients were risperidone LAI (RLAI) and 8 patients were aripiprazole LAI (ALAI)]. However, in this paper, only three cases (one RLAI case and 2 ALAI cases) were selected to illustrate the diffusion effects of both LAI. Dorsogluteal intramuscular (IM) injection sites were measured at prone position using the “double cross” method. Before LAI injection, the distance from the epidermis to the under-fascia (DEUF), and distance from the epidermis to the iliac bone (DEI) at the IM injection site were assessed by using ultrasonography: 1) the injection needle was inserted to the gluteus medius, and 2) observed the diffusion status within the muscle injected RLAI and ALAI were confirmed using the B-mode ultrasonography. Both RLAI and ALAI were depicted as high echogenicity with acoustic shadowing. It was considered that the diffusion states of LAIs by ultrasonography were important time course evaluations providing objective evidence.

Effect of berberine combined with risperidone therapy on endocrine hormones and oxidative stress in patients with schizophrenia

Objective:To study the effect of berberine combined with risperidone therapy on endocrine hormones and oxidative stress in patients with schizophrenia.Methods: A total of 90 patients with schizophrenia who were treated in our hospital between May 2014 and May 2016 were collected, reviewed and then divided into the control group (n=47) who received risperidone therapy and the observation group (n=47) who received berberine combined with risperidone therapy. Serum insulin resistance index levels, thyroid hormone and prolactin contents as well as oxidative stress index contents before and after treatment were compared between two groups of patients.Results: Before treatment, differences in serum insulin resistance index levels, thyroid hormone and prolactin contents as well as oxidative stress index contents were not statistically significant between two groups of patients. After treatment, serum FINS and HOMA-IR levels in observation group were lower than those in control group;serum T3 content was higher than that in control group while PRL content was lower than that in control group;serum MDA content was lower than that in control group while SOD, GSH-Px and CAT contents were higher than those in control group.Conclusion: Berberine combined with risperidone therapy for patients with schizophrenia won't cause severe endocrine hormone level disorder, and helps to reduce the systemic oxidative stress response.

Long-Term Clinical Outcome of Patients Using Risperidone Long-Acting Injectable: The Romanian e-STAR Database

The objectives of e-STAR Romania (NCT00283517) were to collect clinical outcome data of Romania schizophrenia or schizo-affective disorder patients;prospectively to assess the reasons of treatment initiation, medication usage patterns;to document (long-term) clinical efficacy;and to collect safety data, as well as recording 2-year corresponding retrospective data. In total, 378 eligible subjects were enrolled who were initiated either on risperidone long-acting injectable (RLAI) (290) or on an oral antipsychotic (OA) (88) at baseline as required by the local Summary of the Product Characteristics. Data were collected from per patient both retrospectively and prospectively over a 24-month period at 3-month intervals after starting treatment. The results indicated that subjects suffering from schizophrenia or schizo-affective disorder initiated on RLAI were less likely to be hospitalized within the first 24 months after the initiation of treatment. Moreover, subjects treated with RLAI experienced significant improvements in their illness severity and functioning. Discontinuation rates for RLAI were low and doses were stable throughout the 24 months following the initiation of treatment. In addition, the necessity for supplementary concomitant medication was reduced. Adverse events were reported in 20.3% (RLAI) and 11.4% (OA) of the subjects. In general, patients initiated on RLAI and OA at baseline both clinically improved on all assessed parameters but a larger improvement was observed for patients on RLAI. Incidences of reported AEs during the use of RLAI in a naturalistic setting are comparable with those described in clinical studies;however, the incidence of extrapyramidal signs and weight gain was lower than expected.

Population pharmacokinetics of risperidone based on meta-analysis and its application in therapeutic drug monitoring of Chinese schizophrenic patients

Population pharmacokinetic meta-analysis method was used in order to obtain the pharmacokinetic characteristics of risperidone and its active metabolite. Eighteen studies were selected from published papers from 1995 to 2011. A model consisted of two compartments for parent drug and one compartment for its active metabolite combined with a flexible absorption process was developed based on the meta-dataset. The population-predicted apparent clearance for risperidone and 9-hydroxyrisperidone, the active metabolite was 7.66 L/h and 7.38 L/h, and the apparent volume of distribution in the central compartment was 70.6 L and 117 L, respectively. The final model was evaluated by visual predictive check（VPC） based on 1000 times model simulation. This model was adequately used to predict clinical therapeutic drug monitoring（TDM） data from 42 Chinese inpatients. Bias（mean prediction errors, MPE） and precision（root mean squared prediction errors, RMSE） were calculated to statistically analysis the population prediction error. It was demonstrated that the model developed from the meta-dataset was reliable and can be used to facilitate the individualized treatment for a target population.

首发精神分裂症患者服用利培酮治疗后静息态脑功能的研究

目的首发精神分裂症患者服用探讨利培酮治疗前后,静息态脑功能局部一致性变化特点以及与临床症状的关系。方法对30例首发精神分裂症患者(观察组)和30名健康志愿者(对照组)进行静息态脑功能磁共振成像扫描,计算全脑局部一致性的ReHo值并进行比较;治疗前与治疗8周后采用阳性与阴性症状量表(PANSS)和Hoffman幻听评定量表(AHRS)对患者进行临床评定;将患者治疗前后的精神症状量表评分与异常脑区的ReHo值进行相关性分析。结果治疗后,观察组患者PANSS总分及各维度评分、AHRS评分均较治疗前降低(P<0.01)。与对照组志愿者相比,治疗前观察组患者ReHo值降低的脑区主要分布于左颞上回、左颞下回,ReHo值升高的脑区主要分布于双楔前叶、右顶上小叶、右小脑后叶(已校正,P<0.05);治疗后观察组患者ReHo值升高的脑区主要分布于右小脑前叶、右顶上小叶,ReHo值降低的脑区位于左颞下回(已校正,P<0.05)。观察组患者治疗前左颞上回ReHo值与PANSS阳性症状评分和AHRS评分均呈显著负相关(r=-0.433、-0.238,P<0.05)。结论精神分裂症患者的多个脑区存在静息态脑功能异常,左颞上回异常的脑活动与疾病症状有关。