Serum Concentrations Of Risperidone Research Articles

Influence of Kidney Function on Serum Risperidone Concentrations in Patients Treated With Risperidone.

Risperidone is one of the most commonly prescribed antipsychotics worldwide. Its main metabolite, 9-hydroxyrisperidone (9-OH-RIS), is excreted renally. The present study examined the relationship of kidney function and serum risperidone concentrations in a large sample of risperidone-treated patients. Serum concentrations of risperidone and its active metabolite 9-OH-RIS, as well as creatinine concentrations, from which glomerular filtration rates (GFRs) were estimated, were determined in 175 risperidone-medicated patients (75 female, 100 male). Data were collected between July 2013 and December 2016. Patients were clustered in 4 groups according to their estimated GFR (eGFR) (30-60; > 60-90; > 90-120; and > 120 mL/min/1.73 m²), and serum concentrations of risperidone and 9-OH-RIS and their sum (active moiety [AM]) were compared groupwise. Additionally, serum concentrations were correlated with kidney function. Dose-corrected AM and dose-corrected 9-OH-RIS concentrations were significantly higher in patients with an eGFR of 30-60 mL/min/1.73 m² than in patients with an eGFR > 90-120 mL/min/1.73 m² (P < .001 for dose-corrected AM and P = .001 for dose-corrected 9-OH-RIS) or > 120 mL/min/1.73 m² (P = .036 and .021, respectively). Dose-corrected AM levels were more than doubled in the 30-60 mL/min/1.73 m² group compared to the > 90-120 mL/min/1.73 m² group (mean ± SD = 22.2 ± 14.0 [ng/mL]/[mg/d] vs 10.1 ± 7.7 [ng/mL]/[mg/d]). In the total group, eGFR and dose-corrected 9-OH-RIS and dose-corrected AM were weakly but statistically significantly correlated (Spearman rank correlation coefficient [Rs] = -0.2, P = .004, and Rs = -0.17, P = .01, respectively). Kidney function is an important determinant of risperidone clearance. These data suggest reducing the risperidone dose by 50% in patients with a GFR below 60 mL/min.

Serum Concentration of Risperidone and Adverse Effects in Children and Adolescents

Serum Concentration of Risperidone and Adverse Effects in Children and Adolescents

Impact of Ageing on Serum Concentrations of Risperidone and Its Active Metabolite in Patients with Known CYP2D6 Genotype

The aim of this study was to investigate the impact of ageing on serum concentrations of risperidone and 9-hydroxyrisperidone in patients with known CYP2D6 genotype. We included retrospective therapeutic drug monitoring data from 464 genotyped patients with measured serum concentrations of risperidone and 9-hydroxyrisperidone after oral administration. Patients were divided into two age subgroups, that is ≤65 (n = 396) and >65 years (n = 68), and dose-adjusted concentrations (C:D ratios) were compared using multiple linear regression analyses with CYP2D6 genotype and gender as covariates. Moreover, absolute concentrations and prescribed daily doses were compared between age subgroups by simple, univariate Mann-Whitney tests. Age had no effect on C:D ratio of risperidone (p > 0.4), but C:D ratios of 9-hydroxyrisperidone and risperidone + 9-hydroxyrisperidone (total active moiety) were estimated to be 2.6 and 2.0 times higher in patients >65 versus ≤65 years (p < 0.001). Female gender and a CYP2D6 poor metabolizer (PM) genotype were also associated with significantly higher C:D ratio of the total active moiety (p < 0.01). Despite lower dosing in patients >65 versus ≤65 years (median 1.5 versus 3.0 mg/day, p < 0.0001), absolute concentration of the total active moiety did not differ between the age subgroups (median 52.5 versus 47.0 nmol/L, p > 0.6). In conclusion, ageing implies significantly increased dose-adjusted serum concentration of risperidone active moiety, and treatment intensity is not generally reduced by halving the oral dose in the elderly. Tolerability of risperidone therapy should therefore be closely monitored in older patients, and female CYP2D6 PMs >65 years might be a particularly vulnerable subgroup of adverse effects.

Serum Concentrations of Risperidone and Aripiprazole in Subgroups Encoding CYP2D6 Intermediate Metabolizer Phenotype

Cytochrome P450 2D6 intermediate metabolizer phenotype (CYP2D6 IM) comprises various genotype subgroups. The aim of this study was to evaluate serum concentrations of the CYP2D6 substrates risperidone and aripiprazole in psychiatric patients with various CYP2D6 genotypes encoding IM phenotype. The study was based on therapeutic drug monitoring data from CYP2D6-genotyped patients (mainly of white origin) treated with orally administered risperidone (n = 190) or aripiprazole (n = 266). Patients were divided into 3 genotype subgroups encoding IM phenotype: (1) heterozygous carriers of fully functional and nonfunctional variant alleles (*1/def), (2) homozygous carriers of reduced-function variant alleles (red/red), and (3) heterozygous carriers of reduced-function and nonfunctional variant alleles (def/red). Dose-adjusted serum concentrations of risperidone and aripiprazole were compared between the genotype subgroups using *1/def, the most frequent CYP2D6 genotype among these subgroups, as the reference group. Median serum concentrations were 4.5- and 1.6-fold higher in the def/red genotype than the *1/def genotype for risperidone and aripiprazole, respectively (P < 0.01 for both). Correspondingly, the serum concentrations were 3.4- and 1.8-fold higher in the red/red subgroup compared with the reference group (P < 0.05 for both). In conclusion, this study revealed substantial variability in serum concentrations of risperidone and aripiprazole between CYP2D6 genotypes associated with IM phenotype. A considerable phenotypical difference was observed between patients carrying 1 and 2 variant alleles.

The Effect of Coadministration of Duloxetine on Steady-State Serum Concentration of Risperidone and Aripiprazole: A Study Based on Therapeutic Drug Monitoring Data

Previous studies have categorized duloxetine as a moderate inhibitor of CYP2D6. The aim of the present study was to investigate the potential interactions between duloxetine and the two CYP2D6 substrates risperidone and aripiprazole in psychiatric patients. Serum concentration data from patients treated with risperidone (n = 8) or aripiprazole (n = 7) in combination with duloxetine were retrieved from therapeutic drug monitoring files at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. The degree of interaction was assessed by comparing the data with a control group of CYP2D6-genotyped patients (homozygous "extensive metabolizers") using oral risperidone or aripiprazole without duloxetine. Coadministration of duloxetine did not significantly increase the concentration of the parent drug or the parent drug/metabolite ratio of either risperidone or aripiprazole. The present study therefore indicates that duloxetine may safely be used concomitantly with risperidone or aripiprazole.

Induction of Drug Transporters Alters Disposition of Risperidone - A Study in Mice.

Pharmacokinetic interactions, e.g. modulation of drug transporters like P-glycoprotein at the blood-brain barrier, can be a reason for treatment non-response. This study focuses on the influence of induction of drug transporters on the disposition of the antipsychotic drugs risperidone and 9-hydroxyrisperidone. Brain and serum concentrations of risperidone and its active metabolite 9-hydroxyrisperidone, which are known P-glycoprotein substrates, were measured after drug transporter induction with rifampicin, dexamethasone or 5-pregnene-3beta-ol-20-on-16alpha-carbonitrile using high performance liquid chromatography. Disposition of risperidone and 9-hydroxyrisperidone was dramatically decreased in mouse brain and serum after drug transporter induction. The metabolism of risperidone was also affected.

Impact of CYP2D6 Genotype on Steady-State Serum Concentrations of Risperidone and 9-Hydroxyrisperidone in Patients Using Long-Acting Injectable Risperidone

An increased risk of adverse effects and discontinuation of risperidone therapy is observed in patients with impaired cytochrome P450 2D6 (CYP2D6) function on oral risperidone therapy. The present study is the first to investigate the impact of CYP2D6 genotype on serum concentrations of risperidone and 9-hydroxyrisperidone in patients using injectable long-acting risperidone. Two hundred three patients were divided into groups according to administered risperidone formulation (long-acting injection; n = 90) and CYP2D6 genotype. Dose-adjusted serum concentrations were compared using the CYP2D6*1/*1 subgroup as reference. The total serum concentration of risperidone plus 9-hydroxyrisperidone was 80% (P < 0.03) and 32% (P < 0.03) higher, whereas the risperidone-9-hydroxyrisperidone ratios were 6.3-fold (P < 0.01) and 12.5-fold (P < 0.01) higher in the CYP2D6def/def (def means defective allele, ie, CYP2D6*3, *4, *5, or *6) subgroup for long-acting and oral risperidone, respectively. In conclusion, CYP2D6 genotype significantly affects the pharmacokinetics of both oral and long-acting risperidone formulations.

Pharmacokinetics and efficacy of a direct switch from conventional depot to risperidone long‐acting injection in Chinese patients with schizophrenic and schizoaffective disorders

This 12-week open-label study was designed to investigate the pharmacokinetics and efficacy of a direct switch from a conventional depot to long-acting injectable risperidone in patients with schizophrenia and schizoaffective disorder. Men or women from 18 to 65 years old with a diagnosis of schizophrenia or schizoaffective disorder were eligible for participation if they had been treated with conventional depot for at least 8 weeks before study entry. Intramuscular long-acting risperidone was administered starting from 25 mg, with the dose flexibly adjusted every two weeks for 12 weeks from week 4. Of the 25 patients enrolled in this study, 21 completed at least one post-baseline assessment and were thus included in the analysis. The mean serum concentration of risperidone plus 9-hydroxyrisperidone was 29.1 ng/mL at the 12th week after switching, with an average injection dose of 31.25 mg long-acting risperidone every two weeks. The levels of active moiety of risperidone seemed to be higher in Chinese patients compared to those in Caucasian patients. Positive and Negative Syndrome Scale total scores (from 67.5 to 56.4; P = 0.002), scores for negative symptoms (P = 0.006) and general symptoms (P = 0.001) were improved significantly 12 weeks after the switch. Mean Extrapyramidal Symptom Rating Scale scores were improved significantly from 20.1 to 5.5 (P < 0.001). Significantly decreased levels of cholesterol and triglyceride were found at the 12th week. The levels of fasting glucose, low-density lipoprotein, high-density lipoprotein and bodyweight remained unchanged. These findings suggest that switching from conventional depot to long-acting risperidone is feasible with the advantage of symptom reduction and side-effect profile decrement.

Risperidone and Lamotrigine: No Evidence of a Drug Interaction

Article AbstractBecause this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.Sir: It has been suggested that adding lamotrigine to an ongoing treatment with risperidone and clozapine might significantly increase the serum concentration of risperidone.1 However, lamotrigine is not known to inhibit the cytochrome P450 (CYP) enzymes CYP2D6 or CYP3A4, which are the major enzymes involved in the metabolism of risperidone.2To extend the knowledge about this possible drug interaction,we performed a retrospective analysis on data obtainedfrom our routine therapeutic drug monitoring database for risperidoneand its active metabolite 9-hydroxyrisperidone.†‹†‹

Levetiracetam-Induced Depression in a Healthy Adult

Article AbstractBecause this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text.Sir: It has been suggested that adding lamotrigine to an ongoing treatment with risperidone and clozapine might significantly increase the serum concentration of risperidone.1 However, lamotrigine is not known to inhibit the cytochrome P450 (CYP) enzymes CYP2D6 or CYP3A4, which are the major enzymes involved in the metabolism of risperidone.2To extend the knowledge about this possible drug interaction, we performed a retrospective analysis on data obtained from our routine therapeutic drug monitoring database for risperidone and its active metabolite 9-hydroxyrisperidone.†‹†‹

Serum concentrations of risperidone and 9‐OH risperidone following intramuscular injection of long‐acting risperidone compared with oral risperidone medication

To compare serum concentrations of risperidone, 9-hydroxy (OH) risperidone and risperidone plus 9-OH risperidone, as well as the 9-OH risperidone/risperidone ratio in patients receiving depot and oral risperidone. Serum concentrations from 78 patients receiving three different doses of risperidone depot were measured and compared with serum concentrations from 82 patients taking three different doses of oral risperidone. Patients receiving risperidone depot had significantly lower serum concentrations of risperidone plus 9-OH risperidone than patients taking oral risperidone. More interestingly, the 9-OH risperidone/risperidone ratio was also significantly lower in patients receiving risperidone depot than in patients taking oral risperidone. Serum concentrations of risperidone plus 9-OH risperidone may be a rather poor indication of the antipsychotic efficacy of risperidone unless their ratio is also considered.

Pharmacokinetics and bioequivalence evaluation of risperidone in healthy male subjects with different CYP2D6 genotypes

The aim of this study was to evaluate the bioequivalence of risperidone in healthy male subjects representing different CYP2D6 genotypes with respect to risperidone, 9-hydroxyrisperidone (9-OH-risperidone), and active moiety. A total of 506 Korean subjects were genotyped for CYP2D6*10 by means of allele-specific polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Based on the genotype analysis, 24 subjects, 7 homozygous for CYP2D6*1, 10 for *10, and 7 heterozygous for *10, were recruited and received a single oral dose of 2 mg risperidone tablet in this study. Serum concentrations of risperidone and 9-OHrisperidone up to 48 h were simultaneously determined. There were no significant differences of the active moiety, risperidone, and 9-OH-risperidone between the two preparations in AUC0-proportinal to, and Cmax. The 90% confidence intervals (CIs) for the ratio of means of the log-transformed AUC0-proportional to. and Cmax for the active moiety, risperidone, and 9-OH-risperidone were all within the bioequivalence acceptance criteria of 0.80-1.25. The CYP2D6*10 allele particularly was associated with higher serum concentrations of risperidone and the risperidone/9-OH-risperidone ratio compared with the CYP2D6*1 allele. The results demonstrate that the two preparations of risperidone are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice. Furthermore, the pharmacokinetic parameters of risperidone and the risperidone/9-OH-risperidone ratio are highly dependent on the CYP2D6 genotypes.

Prolactin elevation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite

Treatment with the antipsychotic risperidone is frequently associated with hyperprolactinemia. The aim of this study was to evaluate the role of the main compound risperidone and its active 9-hydroxy metabolite on elevating prolactin levels. Twenty patients with psychotic disorders, on therapy with risperidone, were studied. All patients had been receiving risperidone for at least 2.5 months, and the median daily dose of risperidone was 3 mg (range 1-10). Morning serum samples for prolactin were analyzed and investigated in relation to the serum concentrations of risperidone and 9-hydroxyrisperidone. Elevated prolactin levels were found in 17 (85%) of the patients. Levels of prolactin were positively correlated to the 9-hydroxyrisperidone serum concentration (r(s) = 0.48, p = 0.03) and to the daily dose of risperidone (r(s) = 0.51, p = 0.03), but did not correlate to the risperidone serum concentration. The present results suggest that 9-hydroxyrisperidone and not risperidone is the main contributor to the increased serum levels of prolactin observed in many risperidone-treated patients.

Prolactin elevation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite

Objective Treatment with the antipsychotic risperidone is frequently associated with hyperprolactinemia. The aim of this study was to evaluate the role of the main compound risperidone and its active 9-hydroxy metabolite on elevating prolactin levels. Methods Twenty patients with psychotic disorders, on therapy with risperidone, were studied. All patients had been receiving risperidone for at least 2.5 months, and the median daily dose of risperidone was 3 mg (range 1–10). Morning serum samples for prolactin were analyzed and investigated in relation to the serum concentrations of risperidone and 9-hydroxyrisperidone. Results Elevated prolactin levels were found in 17 (85%) of the patients. Levels of prolactin were positively correlated to the 9-hydroxyrisperidone serum concentration (rs = 0.48, p = 0.03) and to the daily dose of risperidone (rs = 0.51, p = 0.03), but did not correlate to the risperidone serum concentration. Conclusion The present results suggest that 9-hydroxyrisperidone and not risperidone is the main contributor to the increased serum levels of prolactin observed in many risperidone-treated patients. Copyright © 2006 John Wiley & Sons, Ltd.

Serum Concentrations of Risperidone and 9-Hydroxyrisperidone After Administration of the Long-Acting Injectable Form of Risperidone

There is limited documentation on the pharmacokinetics of long-acting intramuscular risperidone in a naturalistic setting. The objective of this study was to investigate the concentrations of risperidone and its active metabolite 9-hydroxyrisperidone as well as the concentration/dose (C/D) ratios achieved after intramuscular depot administration in a routine therapeutic drug monitoring setting. Thirty samples were collected from 10 female and 20 male patients receiving depot injections of risperidone. For 6 of the patients, the results could be compared with corresponding data available after previous oral administration of risperidone. In addition, data from a group of 278 patients using oral risperidone were retrieved. The median serum concentrations of risperidone plus 9-hydroxyrisperidone were 38 nmol/L 12-14 days after a intramuscular dose of 25 mg/14 days, 67 nmol/L after a dose of 37.5 mg/14 days, 99 nmol/L after a dose of 50 mg/14 days, and 148 nmol/L after a dose of 75 mg/14 days. The median C/D ratio for risperidone plus 9-hydroxy-risperidone was 22.2 (nmol/L)/(mg/d). In the group on oral medication, the median C/D ratio was 18.6 (nmol/L)/(mg/d). In the 6 patients previously using oral risperidone, switching to depot injections gave an average increase of 33% (range 12%-68%) in the C/D ratio. In conclusion, the authors' data indicate that there are great interindividual differences in the extent to which the daily dose has to be reduced when switching from oral to intramuscular depot administration to achieve the same serum concentrations of risperidone plus 9-hydroxyrisperidone. Because the degree of dose adjustment required for the individual patient so far cannot be predicted, guidance by therapeutic drug monitoring might be helpful.